exenatide and Fatty-Liver

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum that ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) and to cirrhosis. The recommended treatment for this disease includes measures that target obesity and insulin resistance. The present review summarizes the role of newer anti-diabetic agents in treatment of NAFLD.. PubMed, MEDLINE and Ovid databases were searched to identify human studies between January 1990 and January 2013 using specified key words. Original studies that enrolled patients with a diagnosis of NAFLD or NASH and involved use of newer classes of anti-diabetic agents for a duration of at least 3 months were included.. Out of the screened articles, four met eligibility criteria and were included in our review. The classes of newer anti-diabetic medications described were dipeptidyl peptidase IV inhibitors and glucagon-like peptide-1 analogues.. Liraglutide and Exenatide showed improvement in transaminases as well as histology in patients with NASH. Sitagliptin showed improvement in transaminases but limited studies are there to access its effect on histology. Further studies are needed to support use of newer anti-diabetic medications in patients with NAFLD.

Topics: Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Liver; Non-alcoholic Fatty Liver Disease; Peptides; Pyrazines; Sitagliptin Phosphate; Transaminases; Treatment Outcome; Triazoles; Venoms

To conduct a prospective randomized trial to investigate the effect of glucagon-like peptide-1 (GLP-1) analogues on ectopic fat stores.. A total of 44 obese subjects with type 2 diabetes uncontrolled on oral antidiabetic drugs were randomly assigned to receive exenatide or reference treatment according to French guidelines. Epicardial adipose tissue (EAT), myocardial triglyceride content (MTGC), hepatic triglyceride content (HTGC) and pancreatic triglyceride content (PTGC) were assessed 45 min after a standardized meal with 3T magnetic resonance imaging and proton magnetic resonance spectroscopy before and after 26 weeks of treatment.. The study population had a mean glycated haemoglobin (HbA1c) level of 7.5 ± 0.2% and a mean body mass index of 36.1 ± 1.1 kg/m(2) . Ninety five percent had hepatic steatosis at baseline (HTGC ≥ 5.6%). Exenatide and reference treatment led to a similar improvement in HbA1c (-0.7 ± 0.3% vs. -0.7 ± 0.4%; p = 0.29), whereas significant weight loss was observed only in the exenatide group (-5.5 ± 1.2 kg vs. -0.2 ± 0.8 kg; p = 0.001 for the difference between groups). Exenatide induced a significant reduction in EAT (-8.8 ± 2.1%) and HTGC (-23.8 ± 9.5%), compared with the reference treatment (EAT: -1.2 ± 1.6%, p = 0.003; HTGC: +12.5 ± 9.6%, p = 0.007). No significant difference was observed in other ectopic fat stores, PTGC or MTGC. In the group treated with exenatide, reductions in liver fat and EAT were not associated with homeostatic model assessment of insulin resistance index, adiponectin, HbA1c or fructosamin change, but were significantly related to weight loss (r = 0.47, p = 0.03, and r = 0.50, p = 0.018, respectively).. Our data indicate that exenatide is an effective treatment to reduce liver fat content and epicardial fat in obese patients with type 2 diabetes, and these effects are mainly weight loss dependent.

Topics: Adipose Tissue; Diabetes Mellitus, Type 2; Exenatide; Fatty Liver; Female; Glycated Hemoglobin; Heart; Humans; Hypoglycemic Agents; Liver; Magnetic Resonance Imaging; Male; Middle Aged; Myocardium; Obesity; Pancreas; Peptides; Pericardium; Postprandial Period; Proton Magnetic Resonance Spectroscopy; Treatment Outcome; Triglycerides; Venoms

To investigate the effects of exenatide on blood glucose, body weight and hepatic enzymes in patients with type 2 diabetes mellitus (T2DM) and concomitant non-alcoholic fatty liver disease (NAFLD).. One hundred and seventeen patients with T2DM and NAFLD were randomly divided into exenatide group and metformin group. Patients were treated with exenatide and metformin, respectively, for 12 weeks.. After 12 weeks of treatment, body weight, body mass index (BMI), waist-to-hip ratio, HbA1c, FPG, 2-h PPG, ALT, AST, γ-GT, and hs-CRP were significantly reduced, and the AST/ALT ratio and adiponectin were markedly increased in both groups. BMI, waist-to-hip ratio, 2-h PPG, ALT, AST, γ-GT, and hs-CRP were markedly lower, and AST/ALT ratio and adiponectin in the exenatide group were dramatically higher than in the metformin group.. Compared with metformin, exenatide is better to control blood glucose, reduces body weight and improves hepatic enzymes, attenuating NAFLD in patients with T2DM concomitant with NAFLD.

Topics: Adiponectin; Adult; Aged; Alanine Transaminase; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Exenatide; Fatty Liver; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Non-alcoholic Fatty Liver Disease; Peptides; Time Factors; Treatment Outcome; Venoms; Waist-Hip Ratio

Systemic fibroblast growth factor (FGF)21 levels and hepatic FGF21 production are increased in non-alcoholic fatty liver disease patients, suggesting FGF21 resistance. We examined the effects of exenatide on FGF21 in patients with type 2 diabetes and in a diet-induced mouse model of obesity (DIO).. Type 2 diabetes mellitus patients (n = 24) on diet and/or metformin were randomised (using a table of random numbers) to receive additional treatment consisting of pioglitazone 45 mg/day or combined therapy with pioglitazone (45 mg/day) and exenatide (10 μg twice daily) for 12 months in an open label parallel study at the Baylor Clinic.. Twenty-one patients completed the entire study and were included in the analysis. Pioglitazone treatment (n = 10) reduced hepatic fat as assessed by magnetic resonance spectroscopy, despite a significant increase in body weight (Δ = 3.7 kg); plasma FGF21 levels did not change (1.9  ±  0.6 to 2.2  ±  0.6 ng/ml [mean ± SEM]). However, combined pioglitazone and exenatide therapy (n = 11) was associated with a significant reduction of FGF21 levels (2.3  ±  0.5 to 1.1  ±  0.3 ng/ml) and a greater decrease in hepatic fat. Besides weight gain observed in the pioglitazone-treated patients, lower extremity oedema was observed as a side effect in two of the ten patients. Three patients who received pioglitazone and exenatide combination therapy complained of significant nausea that was self-limiting and did not require them to leave the study. In DIO mice, exendin-4 for 4 weeks significantly reduced hepatic triacylglycerol content, decreased hepatic FGF21 protein and mRNA, and enhanced phosphorylation of hepatic AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase, although no significant difference in weight and body fat was observed. Hepatic FGF21 correlated inversely with hepatic AMPK phosphorylation. In type 2 diabetes mellitus, combined pioglitazone and exenatide therapy is associated with a reduction in plasma FGF21 levels, as well as a greater decrease in hepatic fat than that achieved with pioglitazone therapy. In DIO mice, exendin-4 treatment reduces hepatic triacylglycerol and FGF21 protein, and enhances hepatic AMPK phosphorylation, suggesting an improvement of hepatic FGF21 resistance.. ClinicalTrials.gov NCT 01432405.

Topics: Adult; Aged; Animals; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Therapy, Combination; Edema; Exenatide; Fatty Liver; Female; Fibroblast Growth Factors; Humans; Hypoglycemic Agents; Liver; Lower Extremity; Male; Metformin; Mice; Middle Aged; Nausea; Non-alcoholic Fatty Liver Disease; Obesity; Peptides; Pioglitazone; Thiazolidinediones; Venoms

Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Agonists of the glucagon-like peptide-1 receptor (GLP-1R), currently approved to treat type 2 diabetes, hold promise to improve steatosis and even steatohepatitis. However, due to their pleiotropic effects, the mechanisms underlying their protective effect on NAFLD remain elusive. We aimed to investigate these mechanisms using an in vitro model of steatosis treated with the GLP-1R agonist Exendin-4 (Ex-4). We established steatotic HepG2 cells by incubating the cells with 400 µM oleic acid (OA) overnight. Further treatment with 200 nM Ex-4 for 3 h significantly reduced the OA-induced lipid accumulation (p < 0.05). Concomitantly, Ex-4 substantially reduced the expression levels of Fatty Acid-Binding Protein 1 (FABP1) and its primary activator, Forkhead box protein A1 (FOXA1). Interestingly, the silencing of β-catenin with siRNA abolished the effect of Ex-4 on these genes, suggesting dependency on the Wnt/β-catenin pathway. Additionally, after β-catenin silencing, OA treatment significantly increased the expression of nuclear transcription factors SREBP-1 and TCF4, whereas Ex-4 significantly decreased this upregulation. Our findings suggest that direct activation of GLP-1R by Ex-4 reduces OA-induced steatosis in HepG2 cells by reducing fatty acid uptake and transport via FABP1 downregulation.

Topics: Exenatide; Fatty Acid-Binding Proteins; Fatty Liver; Glucagon-Like Peptide-1 Receptor; Hep G2 Cells; Hepatocyte Nuclear Factor 3-alpha; Humans; In Vitro Techniques; Lipid Metabolism; Lipogenesis; Models, Biological; Oleic Acid; Protective Agents; Sterol Regulatory Element Binding Protein 1; Transcription Factor 4; Wnt Signaling Pathway

The hypoglycemic drug GLP-1 receptor agonist can ameliorate hepatic steatosis but the mechanism is not clear. Intake of high fructose leads to non-alcoholic fatty liver disease by stimulating lipid synthesis, and β-catenin is the key molecule for realizing GLP-1 function in extrahepatic tissues; with the discovery of GLP-1 receptor in liver, we speculate that β-catenin might mediate GLP-1 receptor agonist on ameliorating hepatic steatosis induced by high fructose. Wistar rats were fed with high fructose diet for 8 weeks and then treated with GLP-1 receptor agonist exenatide for 4 weeks; the changes of lipid synthesis pathway factors, the expression and nuclear translocation of β-catenin, and the hepatic steatosis of the rats were observed. After the intervention of exenatide, the hepatic steatosis induced by high fructose was improved, the nuclear translocation and expression of β-catenin were facilitated, and the mRNA and protein expression of the upstream regulator SREBP-1 and the downstream key enzymes ACC, FAS and SCD-1 of de novo lipogenesis were down-regulated. GLP-1 receptor agonist may ameliorate hepatic steatosis induced by high fructose by β-catenin regulating de novo lipogenesis pathway. GLP-1 receptor agonist may be a potential new drug for the treatment of non-alcoholic fatty liver disease, and the β-catenin may be an important target for the drug therapy.

Topics: Animals; beta Catenin; Body Weight; Diet; Exenatide; Fatty Liver; Fructose; Glucagon-Like Peptide-1 Receptor; Lipogenesis; Liver; Male; Rats, Wistar

Non-alcoholic fatty liver disease (NAFLD) is a common disease associated with metabolic syndrome and can lead to life-threatening complications like hepatic carcinoma and cirrhosis. Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist antidiabetic drug, has the capacity to overcome insulin resistance and attenuate hepatic steatosis but the specific underlying mechanism is unclear. This study was designed to investigate the underlying molecular mechanisms of exenatide therapy on NAFLD. We used in vivo and in vitro techniques to investigate the protective effects of exenatide on fatty liver via fat mass and obesity associated gene (FTO) in a high-fat (HF) diet-induced NAFLD animal model and related cell culture model. Exenatide significantly decreased body weight, serum glucose, insulin, insulin resistance, serum free fatty acid, triglyceride, total cholesterol, low-density lipoprotein, aspartate aminotransferase, and alanine aminotransferase levels in HF-induced obese rabbits. Histological analysis showed that exenatide significantly reversed HF-induced lipid accumulation and inflammatory changes accompanied by decreased FTO mRNA and protein expression, which were abrogated by PI3K inhibitor LY294002. This study indicated that pharmacological interventions with GLP-1 may represent a promising therapeutic strategy for NAFLD.

Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Blood Glucose; Body Weight; Chromones; Diet, High-Fat; Disease Models, Animal; Eating; Enzyme Inhibitors; Exenatide; Fatty Liver; Gene Expression Regulation; In Vitro Techniques; Insulin; Male; Malondialdehyde; Morpholines; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Peptides; Phosphatidylinositol 3-Kinases; Protective Agents; Rabbits; Superoxide Dismutase; Venoms

Activation of endoplasmic reticulum (ER) stress is involved in the development of nonalcoholic fatty liver disease. Glucagon-like peptide-1 (GLP-1) has been reported to reduce hepatic steatosis, but the underlying mechanism has not been fully elucidated. Here, we investigated whether exendin-4 (EX-4), a GLP-1 receptor analogue, improves hepatic steatosis through ER stress reduction. Furthermore, we explored which ER stress pathway is involved in this process, with a focus on the protein kinase RNA-like ER kinase (PERK)-nuclear factor erythroid-derived 2-related factor 2 (Nrf2) pathway. EX-4 treatment reduced hepatic lipid accumulation by suppressing the expression of lipogenic genes and restoring the expression of β-oxidation genes in palmitate-treated HepG2 cells and high fat diet (HFD)-fed mice. In addition, EX-4 treatment suppressed hepatic ER stress activation in HFD-fed mice and tunicamycin-treated mice. In particular, EX-4 treatment restored HFD- and tunicamycin-induced Nrf2 nuclear translocation to control levels. Inhibition of Nrf2 by siRNA enhanced phosphorylation of PERK and eukaryotic translation initiation factor 2α (eIF2α), as well as other substrates of the PERK pathway. Nrf2 knockdown also inhibited the protective effects of EX-4 against lipid accumulation, ER stress activation, and cell death in palmitate-treated HepG2 cells. EX-4 treatment prevents hepatic steatosis and improves cell survival by regulating hepatic lipid metabolism and reducing ER stress activation, and Nrf2 plays an essential role in the protective effect of GLP-1 on hepatic steatosis.

Topics: Animals; Cell Death; Cell Line; Cell Line, Tumor; Cell Survival; Endoplasmic Reticulum Stress; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Hep G2 Cells; Humans; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2

Recent studies have indicated that lipid-induced endoplasmic reticulum (ER) stress is a major contributor to the progression of hepatic steatosis. Exenatide (exendin-4), a glucagon-like peptide-1 receptor agonist, is known to improve hepatic steatosis, with accumulating evidence. In this study, we investigated whether exenatide could alleviate lipid-induced hepatic ER stress through mammal sirtuin 1 (SIRT1) and illustrated the detailed mechanisms. Male C57BL/6J mice challenged with a high-fat diet (HFD) were treated with exenatide or normal saline by intraperitoneal injection for 4 weeks. We observed that HFD feeding induced hepatic ER stress as indicated by increased expression of glucose-regulated protein 78, phosphorylated protein kinase-like ER kinase, and phosphorylated eukaryotic initiation factor 2α, while these increases were significantly inhibited by exenatide. Exenatide notably decreased the liver weight and hepatic steatosis induced by HFD challenge. Consistently, in human HepG2 cells and primary murine hepatocytes, exendin-4 also significantly alleviated the ER stress and lipid accumulation induced by palmitate. Importantly, further studies showed that exendin-4 enhanced the binding of heat shock factor 1 to the promoter of heat shock protein (HSP) genes through SIRT1-mediated deacetylation, which then increased the expression of molecular chaperones HSP70 and HSP40 to alleviate hepatic ER stress. Finally, inhibition of SIRT1 by genetic whole-body heterozygous knockout or by lentiviral short hairpin RNA knockdown greatly diminished the effect of exenatide on deacetylating heat shock factor 1, increasing HSP expression and alleviating ER stress and hepatic steatosis in HFD-fed mice.. The SIRT1/heat shock factor 1/HSP pathway is essential for exenatide-alleviated, lipid-induced ER stress and hepatic steatosis, which provides evidence for a molecular mechanism to support exenatide and incretin mimetics as promising therapeutics for obesity-induced hepatic steatosis. (Hepatology 2017;66:809-824).

Topics: Animals; Blood Glucose; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Endoplasmic Reticulum Stress; Exenatide; Fatty Liver; Heat-Shock Proteins; Hepatocytes; Humans; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptides; Random Allocation; Sensitivity and Specificity; Signal Transduction; Sirtuin 1; Venoms

To investigate the effects of glucagon-like peptide-1 (GLP-1) receptor agonist, exenatide, on liver function and steatosis in obese mice.. Male c57BL/6J mice (8 weeks old) were divided into high-fat-diet group (for obesity model construction) and chow diet group. 12 weeks later, mice of high-fat diet group were randomly divided into high-dose exenatide group [H group, intraperitoneal injection 0.02 μg/ (g·d) , high-fat-diet], low-dose exenatide group [L group, intraperitoneal injection 0.01 μg/ (g·d) , high-fat-diet], saline group (NS group, intraperitoneal injection of saline, high-fat-diet) , diet control group (D group, shifted to chow diet) and high-fat control group (M group, high-fat-diet) for 4-week treatments , respectively. The body mass and serum biochemical indicators of were detected. Liver tissues were stained with HE, and steatosis score was measured.. After 4-week treatments, H group showed more body mass loss than L group and D group (. High-dose exenatide treatment can effectively reduce body mass of obese mice, but it has little difference when compared with dietary intervention in improving blood fat and liver steatosis.

Topics: Animals; Diet, High-Fat; Exenatide; Fatty Liver; Glucagon-Like Peptide-1 Receptor; Insulin Resistance; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Peptides; Triglycerides; Uric Acid; Venoms

Nonalcoholic fatty liver is characterized by the abnormal accumulation of triglycerides within hepatocytes, resulting in a steatotic liver. Glucagon-like peptide 1 and its analog exendin-4 can ameliorate certain aspects of this syndrome by inducing weight loss and reducing hepatic triglyceride accumulation, but it is unclear whether these effects result from the effects of glucagon-like peptide 1 on the pancreas, or from direct action on the liver. This study investigated the direct action and putative cellular mechanism of exendin-4 on steatotic hepatocytes in culture. Steatosis was induced in cultured HepG2 human hepatoma cells by incubation in media supplemented with 2 mM each of linoleic acid and oleic acid. Steatotic hepatocytes were then pre-incubated in the protein kinase A inhibitor H89 for 30 min, then treated with exendin-4 over a period of 24 h. Cell viability and triglyceride content were characterized by a TUNEL assay and AdipoRed staining, respectively. Our results showed that steatotic cells maintained high levels of intracellular triglycerides (80%) compared to lean controls (25%). Exendin-4 treatment caused a significant reduction in intracellular triglyceride content after 12 h that persisted through 24 h, while protein kinase A inhibitors abolished the effects of exendin-4. The results demonstrate the exendin-4 induces a partial reduction in triglycerides in steatotic hepatocytes within 12 h via the GLP-1 receptor-mediated activation of protein kinase A. Thus, the reduction in hepatocyte triglyceride accumulation is likely driven primarily by downregulation of lipogenesis and upregulation of β-oxidation of free fatty acids.

Topics: Carcinoma, Hepatocellular; Cell Survival; Cyclic AMP-Dependent Protein Kinases; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Hep G2 Cells; Hepatocytes; Humans; Isoquinolines; Linoleic Acid; Lipogenesis; Liver Neoplasms; Oleic Acid; Pancreas; Peptides; Sulfonamides; Triglycerides; Venoms

Perturbations in hepatic lipid and very-low-density lipoprotein (VLDL) metabolism are involved in the pathogenesis of obesity and hepatic insulin resistance. The objective of this study is to delineate the mechanism of subdiaphragmatic vagotomy in preventing obesity, hyperlipidemia, and insulin resistance.. By subjecting the complete subdiaphragmatic vagotomized mice to various nutritional conditions and investigating hepatic de novo lipogenesis pathway, we found that complete disruption of subdiaphragmatic vagal signaling resulted in a significant decrease of circulating VLDL-triglyceride compared with the mice obtained sham procedure. Vagotomy further prevented overproduction of VLDL-triglyceride induced by an acute fat load and a high-fat diet-induced obesity, hyperlipidemia, hepatic steatosis, and glucose intolerance. Mechanistic studies revealed that plasma glucagon-like peptide-1 was significantly raised in the vagotomized mice, which was associated with significant reductions in mRNA and protein expression of SREBP-1c (sterol regulatory element-binding protein 1c), SCD-1 (stearoyl-CoA desaturase-1), and FASN (fatty acid synthase), as well as enhanced hepatic insulin sensitivity. In vitro, treating mouse primary hepatocytes with a glucagon-like peptide-1 receptor agonist, exendin-4, for 48 hours inhibited free fatty acid, palmitic acid treatment induced de novo lipid synthesis, and VLDL secretion from hepatocytes.. Elevation of glucagon-like peptide-1 in vagotomized mice may prevent VLDL overproduction and insulin resistance induced by high-fat diet. These novel findings, for the first time, delineate an intrinsic gut-liver regulatory circuit that is mediated by glucagon-like peptide-1 in regulating hepatic energy metabolism.

Topics: Animals; Biomarkers; Blood Glucose; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Exenatide; Fatty Acid Synthase, Type I; Fatty Liver; Gene Expression Regulation; Glucagon-Like Peptide 1; Hepatocytes; Hyperlipidemias; Incretins; Insulin; Insulin Resistance; Intestinal Mucosa; Intestines; Lipoproteins, VLDL; Liver; Male; Mice, Inbred C57BL; Obesity; Peptides; RNA, Messenger; Signal Transduction; Stearoyl-CoA Desaturase; Sterol Regulatory Element Binding Protein 1; Time Factors; Triglycerides; Up-Regulation; Vagotomy; Vagus Nerve; Venoms

Donor organ shortages have led to an increased interest in finding new approaches to recover organs from extended criteria donors (ECD). Normothermic extracorporeal liver perfusion (NELP) has been proposed as a superior preservation method to reduce ischemia/reperfusion injury (IRI), precondition suboptimal grafts, and treat ECD livers so that they can be successfully used for transplantation. The aim of this study was to investigate the beneficial effects of a modified NELP circuit on discarded human livers. Seven human livers that were rejected for transplantation were placed on a modified NELP circuit for 8 hours. Perfusate samples and needle core biopsies were obtained at hourly intervals. A defatting solution that contained exendin-4 (50 nM) and L-carnitine (10 mM) was added to the perfusate for 2 steatotic livers. NELP provided normal temperature, electrolytes, and pH and glucose levels in the perfusate along with physiological vascular flows and pressures. Functional, biochemical, and microscopic evaluation revealed no additional injuries to the grafts during NELP with an improved oxygen extraction ratio (>0.5) and stabilized markers of hepatic injury. All livers synthesized adequate amounts of bile and coagulation factors. We also demonstrated a mild reduction (10%) of macroglobular steatosis with the use of the defatting solution. Histology demonstrated normal parenchymal architecture and a minimal to complete lack of IRI at the end of NELP. In conclusion, a modified NELP circuit preserved hepatocyte architecture, recovered synthetic functions, and hepatobiliary parameters of ECD livers without additional injuries to the grafts. This approach has the potential to increase the donor pool for clinical transplantation. Liver Transplantation 22 979-993 2016 AASLD.

Topics: Adult; Aged; Allografts; Biopsy, Large-Core Needle; Carnitine; Donor Selection; Exenatide; Fatty Liver; Female; Humans; Liver; Liver Transplantation; Male; Middle Aged; Organ Preservation; Organ Preservation Solutions; Peptides; Perfusion; Reperfusion Injury; Temperature; Tissue Survival; Venoms; Warm Ischemia

The release of Ca(2+) from the endoplasmic reticulum (ER) and subsequent replenishment of ER Ca(2+) by Ca(2+) entry through store-operated Ca(2+) channels (SOCE) play critical roles in the regulation of liver metabolism by adrenaline, glucagon and other hormones. Both ER Ca(2+) release and Ca(2+) entry are severely inhibited in steatotic hepatocytes. Exendin-4, a slowly-metabolised glucagon-like peptide-1 (GLP-1) analogue, is known to reduce liver glucose output and liver lipid, but the mechanisms involved are not well understood. The aim of this study was to determine whether exendin-4 alters intracellular Ca(2+) homeostasis in steatotic hepatocytes, and to evaluate the mechanisms involved. Exendin-4 completely reversed lipid-induced inhibition of SOCE in steatotic liver cells, but did not reverse lipid-induced inhibition of ER Ca(2+) release. The action of exendin-4 on Ca(2+) entry was rapid in onset and was mimicked by GLP-1 or dibutyryl cyclic AMP. In steatotic liver cells, exendin-4 caused a rapid decrease in lipid (half time 6.5min), inhibited the accumulation of lipid in liver cells incubated in the presence of palmitate plus the SOCE inhibitor BTP-2, and enhanced the formation of cyclic AMP. Hormone-stimulated accumulation of extracellular glucose in glycogen replete steatotic liver cells was inhibited compared to that in non-steatotic cells, and this effect of lipid was reversed by exendin-4. It is concluded that, in steatotic hepatocytes, exendin-4 reverses the lipid-induced inhibition of SOCE leading to restoration of hormone-regulated cytoplasmic Ca(2+) signalling. The mechanism may involve GLP-1 receptors, cyclic AMP, lipolysis, decreased diacylglycerol and decreased activity of protein kinase C.

Topics: Animals; Bucladesine; Calcium; Calcium Signaling; Cyclic AMP; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Hepatocytes; Hormones; Intracellular Space; Palmitic Acid; Peptides; Rats, Zucker; Venoms

Cardiovascular complications of obesity and diabetes are major health problems. Assessing their development, their link with ectopic fat deposition and their flexibility with therapeutic intervention is essential. The aim of this study was to longitudinally investigate cardiac alterations and ectopic fat accumulation associated with diet-induced obesity using multimodal cardiovascular magnetic resonance (CMR) in mice. The second objective was to monitor cardiac response to exendin-4 (GLP-1 receptor agonist).. Male C57BL6R mice subjected to a high fat (35 %) high sucrose (34 %) (HFHSD) or a standard diet (SD) during 4 months were explored every month with multimodal CMR to determine hepatic and myocardial triglyceride content (HTGC, MTGC) using proton MR spectroscopy, cardiac function with cine cardiac MR (CMR) and myocardial perfusion with arterial spin labeling CMR. Furthermore, mice treated with exendin-4 (30 μg/kg SC BID) after 4 months of diet were explored before and 14 days post-treatment with multimodal CMR.. HFHSD mice became significantly heavier (+33 %) and displayed glucose homeostasis impairment (1-month) as compared to SD mice, and developed early increase in HTGC (1 month, +59 %) and MTGC (2-month, +63 %). After 3 months, HFHSD mice developed cardiac dysfunction with significantly higher diastolic septum wall thickness (sWtnD) (1.28 ± 0.03 mm vs. 1.12 ± 0.03 mm) and lower cardiac index (0.45 ± 0.06 mL/min/g vs. 0.68 ± 0.07 mL/min/g, p = 0.02) compared to SD mice. A significantly lower cardiac perfusion was also observed (4 months:7.5 ± 0.8 mL/g/min vs. 10.0 ± 0.7 mL/g/min, p = 0.03). Cardiac function at 4 months was negatively correlated to both HTGC and MTGC (p < 0.05). 14-day treatment with Exendin-4 (Ex-4) dramatically reversed all these alterations in comparison with placebo-treated HFHSD. Ex-4 diminished myocardial triglyceride content (-57.8 ± 4.1 %), improved cardiac index (+38.9 ± 10.9 %) and restored myocardial perfusion (+52.8 ± 16.4 %) under isoflurane anesthesia. Interestingly, increased wall thickness and hepatic steatosis reductions were independent of weight loss and glycemia decrease in multivariate analysis (p < 0.05).. CMR longitudinal follow-up of cardiac consequences of obesity and diabetes showed early accumulation of ectopic fat in mice before the occurrence of microvascular and contractile dysfunction. This study also supports a cardioprotective effect of glucagon-like peptide-1 receptor agonist.

Topics: Adiposity; Animals; Blood Glucose; Coronary Circulation; Diabetes Mellitus; Diet, High-Fat; Dietary Sucrose; Disease Models, Animal; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Heart Diseases; Liver; Magnetic Resonance Imaging, Cine; Male; Mice, Inbred C57BL; Multimodal Imaging; Multivariate Analysis; Myocardial Contraction; Myocardial Perfusion Imaging; Myocardium; Obesity; Peptides; Predictive Value of Tests; Proton Magnetic Resonance Spectroscopy; Recovery of Function; Time Factors; Triglycerides; Venoms; Ventricular Function; Weight Gain

The aetiology of inflammation in the liver and vessel wall, leading to non-alcoholic steatohepatitis (NASH) and atherosclerosis, respectively, shares common mechanisms including macrophage infiltration. To treat both disorders simultaneously, it is highly important to tackle the inflammatory status. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces hepatic steatosis and has been suggested to reduce atherosclerosis; however, its effects on liver inflammation are underexplored. Here, we tested the hypothesis that exendin-4 reduces inflammation in both the liver and vessel wall, and investigated the common underlying mechanism.. Female APOE*3-Leiden.CETP mice, a model with human-like lipoprotein metabolism, were fed a cholesterol-containing Western-type diet for 5 weeks to induce atherosclerosis and subsequently treated for 4 weeks with exendin-4.. Exendin-4 modestly improved dyslipidaemia, but markedly decreased atherosclerotic lesion severity and area (-33%), accompanied by a reduction in monocyte adhesion to the vessel wall (-42%) and macrophage content in the plaque (-44%). Furthermore, exendin-4 reduced hepatic lipid content and inflammation as well as hepatic CD68⁺ (-18%) and F4/80⁺ (-25%) macrophage content. This was accompanied by less monocyte recruitment from the circulation as the Mac-1⁺ macrophage content was decreased (-36%). Finally, exendin-4 reduced hepatic chemokine expression in vivo and suppressed oxidized low-density lipoprotein accumulation in peritoneal macrophages in vitro, effects dependent on the GLP-1 receptor.. Exendin-4 reduces inflammation in both the liver and vessel wall by reducing macrophage recruitment and activation. These data suggest that exendin-4 could be a valuable strategy to treat NASH and atherosclerosis simultaneously.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apolipoprotein E3; Atherosclerosis; Cholesterol Ester Transfer Proteins; Diet, Atherogenic; Disease Models, Animal; Drug Implants; Dyslipidemias; Endothelium, Vascular; Exenatide; Fatty Liver; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypolipidemic Agents; Liver; Macrophage Activation; Macrophages; Mice; Mice, Transgenic; Non-alcoholic Fatty Liver Disease; Peptides; Random Allocation; Receptors, Glucagon; Venoms

The aims of the study were to evaluate (1) detection of cognitive function changing in rat with hepatosteatosis model and (2) evaluate the effect of GLP-1 analog (exenatide) on cognitive function in hepatosteatosis. In the study group, 30% fructose was given in nutrition water to perform hepatosteatosis for 8 weeks to 18 male rats. Six male rats were chosen as control group and had normal nutrition. Fructose nutrition group were stratified into 3 groups. In first group (n = 6), intracerebroventricular (ICV) infusion of exenatide (n = 6) was given. ICV infusion of NaCl (n = 6) was given to second group. And also, the third group had no treatment. And also, rats were evaluated for passive avoidance learning (PAL) and liver histopathology. Mean levels of latency time were statistically significantly decreased in rats with hepatosteatosis than those of normal rats (P < 0.00001). However, mean level of latency time in rats with hepatosteatosis treated with ICV exenatide was statistically significantly increased than that of rats treated with ICV NaCl (P < 0.001). Memory performance falls off in rats with hepatosteatosis feeding on fructose (decreased latency time). However, GLP-1 ameliorates cognitive functions (increased latency time) in rats with hepatosteatosis and releated metabolic syndrome.

Topics: Animals; Cognition; Disease Models, Animal; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Hypoglycemic Agents; Male; Peptides; Rats; Venoms

GLP-1 and incretin mimetics, such as exenatide, have been shown to attenuate hepatocyte steatosis in vivo and in vitro, but the specific underlying mechanism is unclear. SIRT1, an NAD(+)-dependent protein deacetylase, has been considered as a crucial regulator in hepatic lipid homeostasis by accumulated studies. Here, we speculate that SIRT1 might mediate the effect of the GLP-1 receptor agonist exenatide (exendin-4) on ameliorating hepatic steatosis. After 8 weeks of exenatide treatment in male SIRT1(+/-) mice challenged with a high-fat diet and their wild-type (WT) littermates, we found that lipid deposition and inflammation in the liver, which were improved dramatically in the WT group, diminished in SIRT1(+/-) mice. In addition, the protein expression of SIRT1 and phosphorylated AMPK was upregulated, whereas lipogenic-related protein, including SREBP-1c and PNPLA3, was downregulated in the WT group after exenatide treatment. However, none of these changes were observed in SIRT1(+/-) mice. In HepG2 cells, exendin-4-reversed lipid deposition induced by palmitate was hampered when SIRT1 was silenced by SIRT1 RNA interference. Our data demonstrate that SIRT1 mediates the effect of exenatide on ameliorating hepatic steatosis, suggesting the GLP-1 receptor agonist could serve as a potential drug for nonalcoholic fatty liver disease (NAFLD), especially in type 2 diabetes combined with NAFLD, and SIRT1 could be a therapeutic target of NAFLD.

Topics: Animals; Diabetes Mellitus, Type 2; Exenatide; Fatty Liver; Glucagon-Like Peptide-1 Receptor; Male; Mice; Non-alcoholic Fatty Liver Disease; Peptides; Receptors, Glucagon; RNA Interference; Sirtuin 1; Venoms

Although understanding the relation between psychotic behavior and immune abnormalities has been the focus of research for many years, it remains to be elucidated whether the changes in cytokine levels are part of etiology or a result of the stress associated with the disorder. In accordance with previous studies on changes in cytokine levels due to metabolic changes and psychosis, we hypothesized that fatty liver may potentiate apomorphine-induced stereotypy in a rodent model and that a synthetic glucagon-like peptide-1 analog exenatide would ameliorate this effect. In this study, 18 male Sprague Dawley albino mature rats were used. We induced hepatosteatosis in these rats by feeding them with 30% fructose dissolved in drinking water for 8 weeks. The animals were divided into three groups, namely, the normal group, the intracerebroventricular (ICV) exenatide group, and the ICV NaCl group. Apomorphine-induced stereotypic behavior test was performed in all groups and the liver was removed for histopathological examination after all the rats were euthanized. In the nonalcoholic fatty liver (NAFL) group, stereotypy scores were significantly increased compared with the control group rats (p < 0.00001). A significant decrease in stereotypy scores were observed in the ICV exenatide group with NAFL when compared with the ICV saline group with NAFL (p < 0.005). In addition, brain malondialdehyde and tumor necrosis factor-α levels decreased in the ICV exenatide group. The results of this study showed that fatty liver enhances the effect of apomorphine on stereotypy, which was reversed by exenatide possibly by antioxidant and anti-inflammatory effects.

Topics: Animals; Brain; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Liver; Male; Malondialdehyde; Peptides; Rats, Sprague-Dawley; Stereotyped Behavior; Tumor Necrosis Factor-alpha; Venoms

The aim of this study was to examine the effects of a new sustained-release (SR) microsphere formulation of exenatide, DA-3091, on body weight gain and hepatic injury in high fat diet (HFD)-induced obese mice and high sucrose diet (HSD)-induced non-alcoholic fatty liver disease (NAFLD) mice. Then, we determined whether DA-3091 has the potency as a drug for the treatment of metabolic disease. In obese mice, after 8-week treatment, the body weight gain was significantly more suppressed by both 1 mg/kg and 2 mg/kg of DA-3091, monthly subcutaneous administered, than by 10 mg/kg/day of sibutramin, a drug against obesity. In NAFLD mice, a significant reduction in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, representative markers of hepatic injury, was observed after biweekly subcutaneous administration of 1 mg/kg and 2 mg/kg of DA-3091 for 8 weeks. A significant reduction in hepatic lipid accumulation was observed in DA-3091 treated groups as well. Based on these results, it is demonstrated that DA-3091 has the potency as a drug for the treatment of metabolic disease.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Glucose; Body Weight; Cholesterol; Delayed-Action Preparations; Dietary Fats; Endotoxins; Exenatide; Fatty Liver; Hypoglycemic Agents; Liver; Liver Function Tests; Male; Mice; Mice, Inbred C57BL; Microspheres; Non-alcoholic Fatty Liver Disease; Obesity; Organ Size; Peptides; Prodrugs; Sucrose; Venoms

The glucokinase activators improve the fasting as well as postprandial glucose control and are important investigational drugs for the treatment of diabetes. However, recent studies have implicated that continuous activation of glucokinase with a small molecule activator can increase hepatic triglycerides and the long term glucose control is not achieved. In this study, we investigated the effect of combination of glucokinase activator (GKA, Piragliatin) with GLP-1 receptor agonist exendin-4 (Ex-4) in male db/db mice. Twelve weeks combination treatment in the db/db mice resulted in a significant decrease in body weight gain, food consumption, random glucose and %HbA1c. The decrease in serum glucose and %HbA1c in combination group was more profound and significantly different than that of individual treatment (GKA or Ex-4) group. GKA treatment increased hepatic triglycerides, whereas combination of Ex-4 with GKA attenuated hepatic steatosis. The combination of GKA with Ex-4 reduced the hepatic lipid accumulation, improved the insulin sensitivity, and reduced hepatic glucose production in db/db mice. Overall, our data indicate that combination of GKA and GLP-1 receptor agonist Ex-4 improves glucose homeostasis, shows antiobesity activity, without causing harmful side effects like fatty liver.

Topics: Animals; Benzeneacetamides; Body Weight; Drug Synergism; Eating; Enzyme Activation; Exenatide; Fatty Liver; Glucokinase; Glucose; Glycogen; Homeostasis; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Liver; Male; Mice; Mice, Inbred C57BL; Peptides; Venoms

The effects of exendin-4 on Sirt1 expression as a mechanism of reducing fatty liver have not been previously reported. Therefore, we investigated whether the beneficial effects of exendin-4 treatment on fatty liver are mediated via Sirt1 in high-fat (HF) diet-induced obese C57BL/6J mice and related cell culture models. Exendin-4 treatment decreased body weight, serum free fatty acid (FA), and triglyceride levels in HF-induced obese C57BL/6J mice. Histological analysis showed that exendin-4 reversed HF-induced hepatic accumulation of lipids and inflammation. Exendin-4 treatment increased mRNA and protein expression of Sirt1 and its downstream factor, AMPK, in vivo and also induced genes associated with FA oxidation and glucose metabolism. In addition, a significant increase in the hepatic expression of Lkb1 and Nampt mRNA was observed in exendin-4-treated groups. We also observed increased expression of phospho-Foxo1 and GLUT2, which are involved in hepatic glucose metabolism. In HepG2 and Huh7 cells, mRNA and protein expressions of GLP-1R were increased by exendin-4 treatment in a dose-dependent manner. Exendin-4 enhanced protein expression of Sirt1 and phospho-AMPKα in HepG2 cells treated with 0.4 mM palmitic acid. We also found that Sirt1 was an upstream regulator of AMPK in hepatocytes. A novel finding of this study was the observation that expression of GLP-1R is proportional to exendin-4 concentration and exendin-4 could attenuate fatty liver through activation of Sirt1.

Topics: AMP-Activated Protein Kinases; Animals; Body Weight; Cell Line, Tumor; Cytokines; Diet, High-Fat; Exenatide; Fatty Liver; Feeding Behavior; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Glucose; Homeostasis; Humans; Lipogenesis; Liver; Mice; Mice, Inbred C57BL; Mice, Obese; Nicotinamide Phosphoribosyltransferase; Oxidation-Reduction; Palmitic Acid; Peptides; Protein Serine-Threonine Kinases; Receptors, Glucagon; Sirtuin 1; Triglycerides; Venoms

Nonalcoholic fatty liver disease is an increasingly prevalent spectrum of conditions characterized by excess fat deposition within hepatocytes. Affected hepatocytes are known to be highly susceptible to ischemic insults, responding to injury with increased cell death, and commensurate liver dysfunction. Numerous clinical circumstances lead to hepatic ischemia. Mechanistically, specific means of reducing hepatic vulnerability to ischemia are of increasing clinical importance. In this study, we demonstrate that the glucagon-like peptide-1 receptor agonist Exendin 4 (Ex4) protects hepatocytes from ischemia reperfusion injury by mitigating necrosis and apoptosis. Importantly, this effect is more pronounced in steatotic livers, with significantly reducing cell death and facilitating the initiation of lipolysis. Ex4 treatment leads to increased lipid droplet fission, and phosphorylation of perilipin and hormone sensitive lipase - all hallmarks of lipolysis. Importantly, the protective effects of Ex4 are seen after a short course of perioperative treatment, potentially making this clinically relevant. Thus, we conclude that Ex4 has a role in protecting lean and fatty livers from ischemic injury. The rapidity of the effect and the clinical availability of Ex4 make this an attractive new therapeutic approach for treating fatty livers at the time of an ischemic insult.

Topics: 3T3-L1 Cells; Adiposity; Animals; Apoptosis; Carrier Proteins; Cell Line, Tumor; Exenatide; Fatty Liver; Glucagon-Like Peptide-1 Receptor; Hepatocytes; Humans; Lipolysis; Liver; Male; Mice; Mice, Inbred C57BL; Necrosis; Peptides; Perilipin-1; Phosphoproteins; Phosphorylation; Protective Agents; Receptors, Glucagon; Reperfusion Injury; Sterol Esterase; Thinness; Venoms

In addition to improve glucose intolerance, recent studies suggest that glucagon-like peptide-1 (GLP-1) receptor agonism also decreases triglyceride (TG) levels. The aim of this study was to evaluate the effect of GLP-1 receptor agonism on very-low-density lipoprotein (VLDL)-TG production and liver TG metabolism.. The GLP-1 peptide analogues CNTO3649 and exendin-4 were continuously administered subcutaneously to high fat diet-fed APOE*3-Leiden transgenic mice. After 4 weeks, hepatic VLDL production, lipid content, and expression profiles of selected genes involved in lipid metabolism were determined.. CNTO3649 and exendin-4 reduced fasting plasma glucose (up to -30% and -28% respectively) and insulin (-43% and -65% respectively). In addition, these agents reduced VLDL-TG production (-36% and -54% respectively) and VLDL-apoB production (-36% and -43% respectively), indicating reduced production of VLDL particles rather than reduced lipidation of apoB. Moreover, they markedly decreased hepatic content of TG (-39% and -55% respectively), cholesterol (-30% and -55% respectively), and phospholipids (-23% and -36% respectively), accompanied by down-regulation of expression of genes involved in hepatic lipogenesis (Srebp-1c, Fasn, Dgat1) and apoB synthesis (Apob).. GLP-1 receptor agonism reduces VLDL production and hepatic steatosis in addition to an improvement of glycemic control. These data suggest that GLP-receptor agonists could reduce hepatic steatosis and ameliorate dyslipidemia in patients with type 2 diabetes mellitus.

Topics: Animals; Apolipoprotein E3; Apolipoproteins B; Blood Glucose; Diabetes Mellitus, Type 2; Dyslipidemias; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Insulin; Lipogenesis; Liver; Male; Mice; Mice, Transgenic; Peptides; Receptors, Glucagon; Venoms

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are effective for obese patients with type 2 diabetes mellitus (T2DM) because they concomitantly target obesity and dysglycaemia. Considering the high prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with T2DM, we determined the impact of 6 months' GLP-1 RA therapy on intrahepatic lipid (IHL) in obese, T2DM patients with hepatic steatosis, and evaluated the inter-relationship between changes in IHL with those in glycosylated haemoglobin (HbA(1)c), body weight, and volume of abdominal visceral and subcutaneous adipose tissue (VAT and SAT). We prospectively studied 25 (12 male) patients, age 50±10 years, BMI 38.4±5.6 kg/m(2) (mean ± SD) with baseline IHL of 28.2% (16.5 to 43.1%) and HbA(1)c of 9.6% (7.9 to 10.7%) (median and interquartile range). Patients treated with metformin and sulphonylureas/DPP-IV inhibitors were given 6 months GLP-1 RA (exenatide, n = 19; liraglutide, n = 6). IHL was quantified by liver proton magnetic resonance spectroscopy ((1)H MRS) and VAT and SAT by whole body magnetic resonance imaging (MRI). Treatment was associated with mean weight loss of 5.0 kg (95% CI 3.5,6.5 kg), mean HbA(1c) reduction of 1·6% (17 mmol/mol) (0·8,2·4%) and a 42% relative reduction in IHL (-59.3, -16.5%). The relative reduction in IHL correlated with that in HbA(1)c (ρ = 0.49; p = 0.01) but was not significantly correlated with that in total body weight, VAT or SAT. The greatest IHL reduction occurred in individuals with highest pre-treatment levels. Mechanistic studies are needed to determine potential direct effects of GLP-1 RA on human liver lipid metabolism.

Topics: Adiposity; Adult; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Fatty Liver; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Liver; Male; Middle Aged; Obesity; Peptides; Prospective Studies; Venoms; Weight Loss

The aim of the present study was to test the effect of sitagliptin and exendin-4 upon metabolic alterations, β-cell mass decrease and hepatic steatosis induced by F (fructose) in rats. Normal adult male Wistar rats received a standard commercial diet without (C) or with 10% (w/v) F in the drinking water (F) for 3 weeks; animals from each group were randomly divided into three subgroups: untreated (C and F) and simultaneously receiving either sitagliptin (CS and FS; 115.2 mg/day per rat) or exendin-4 (CE and FE; 0.35 nmol/kg of body weight, intraperitoneally). Water and food intake, oral glucose tolerance, plasma glucose, triacylglycerol (triglyceride), insulin and fructosamine concentration, HOMA-IR [HOMA (homoeostasis model assessment) for insulin resistance], HOMA-β (HOMA for β-cell function) and liver triacylglycerol content were measured. Pancreas immunomorphometric analyses were also performed. IGT (impaired glucose tolerance), plasma triacylglycerol, fructosamine and insulin levels, HOMA-IR and HOMA-β indexes, and liver triacylglycerol content were significantly higher in F rats. Islet β-cell mass was significantly lower in these rats, due to an increase in the percentage of apoptosis. The administration of exendin-4 and sitagliptin to F animals prevented the development of all the metabolic disturbances and the changes in β-cell mass and fatty liver. Thus these compounds, useful in treating Type 2 diabetes, would also prevent/delay the progression of early metabolic and tissue markers of this disease.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Diet; Dipeptidyl-Peptidase IV Inhibitors; Drinking; Drug Evaluation, Preclinical; Eating; Exenatide; Fatty Liver; Fructose; Glucose Tolerance Test; Hypoglycemic Agents; Insulin-Secreting Cells; Male; Metabolic Syndrome; Peptides; Pyrazines; Rats; Rats, Wistar; Sitagliptin Phosphate; Triazoles; Venoms

Diet composition alters the metabolic states of adipocytes and hepatocytes in diabetes. The effects of dipeptidyl peptidase-4 (DPP-4) inhibition on adipose tissue inflammation and fatty liver have been obscure. We investigated the extrapancreatic effects of DPP-4 inhibition on visceral fat and the liver.. We investigated diet-induced metabolic changes in β-cell-specific glucokinase haploinsufficient (Gck(+/-)) diabetic mice. We challenged animals with a diet containing a combination of sucrose and oleic acid (SO) or sucrose and linoleic acid (SL). Next, we assessed the effects of a DPP-4 inhibitor, des-fluoro-sitagliptin, on adipose tissue inflammation and hepatic steatosis.. The epididymal fat weight and serum leptin level were significantly higher in Gck(+/-) mice fed SL than in mice fed SO, although no significant differences in body weight or adipocyte size were noted. Compared with SO, SL increased the numbers of CD11c(+) M1 macrophages and CD8(+) T-cells in visceral adipose tissue and the expression of E-selectin, P-selectin, and plasminogen activator inhibitor-1 (PAI-1). DPP-4 inhibition significantly prevented adipose tissue infiltration by CD8(+) T-cells and M1 macrophages and decreased the expression of PAI-1. The production of cytokines by activated T-cells was not affected by DPP-4 inhibition. Furthermore, DPP-4 inhibition prevented fatty liver in both wild-type and Gck(+/-) mice. DPP-4 inhibition also decreased the expressions of sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase-1, and fatty acid synthase, and increased the expression of peroxisome proliferator-activated receptor-α in the liver.. Our findings indicated that DPP-4 inhibition has extrapancreatic protective effects against diet-induced adipose tissue inflammation and hepatic steatosis.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Chemokine CCL2; Dietary Fats; Dietary Sucrose; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Enzyme-Linked Immunosorbent Assay; Exenatide; Fatty Liver; Female; Glucokinase; Hypertrophy; Insulin; Interferon-gamma; Interleukin-10; Liver; Male; Mice; Peptides; Polymerase Chain Reaction; Triglycerides; Tumor Necrosis Factor-alpha; Venoms

High-fat dietary intake and low physical activity lead to insulin resistance, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Recent studies have shown an effect of glucagon-like peptide-1 (GLP-1) on hepatic glucose metabolism, although GLP-1 receptors (GLP-1r) have not been found in human livers. The aim of this study was to investigate the presence of hepatic GLP-1r and the effect of exenatide, a GLP-1 analogue, on hepatic signalling.. The expression of GLP-1r was evaluated in human liver biopsies and in the livers of high-fat diet-treated rats. The effect of exenatide (100 nM) was evaluated in hepatic cells of rats fed 3 months with the high-fat diet.. GLP-1r is expressed in human hepatocytes, although reduced in patients with NASH. Similarly, in rats with NASH resulted from 3 months of the high-fat diet, we found a decreased expression of GLP-1r and peroxisome proliferator-activated receptor γ (PPARγ), and reduced peroxisome proliferator-activated receptor α (PPARα) activity. Incubation of hepatocytes with exenatide increased PPARγ expression, which also exerted an insulin-sensitizing action by reducing JNK phosphorylation. Moreover, exenatide increased protein kinase A (PKA) activity, Akt and AMPK phosphorylation and determined a PKA-dependent increase of PPARα activity.. GLP-1 has a direct effect on hepatocytes, by activating genes involved in fatty acid β-oxidation and insulin sensitivity. GLP-1 analogues could be a promising treatment approach to improve hepatic insulin resistance in patients with NAFLD/NASH.

Topics: AMP-Activated Protein Kinases; Animals; Biopsy; Cyclic AMP-Dependent Protein Kinases; Dietary Fats; Disease Models, Animal; Exenatide; Fatty Acids; Fatty Liver; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Hep G2 Cells; Hepatocytes; Humans; Hypoglycemic Agents; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Liver; Male; Non-alcoholic Fatty Liver Disease; Oxidation-Reduction; Peptides; Phosphorylation; PPAR alpha; PPAR gamma; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Signal Transduction; Time Factors; Venoms

Nonalcoholic fatty liver disease (NAFLD) is a known outcome of hepatosteatosis. Free fatty acids (FFA) induce the unfolded protein response (UPR) or endoplasmic reticulum (ER) stress that may induce apoptosis. Recent data indicate ER stress to be a major player in the progression of fatty liver to more aggressive lesions. Autophagy on the other hand has been demonstrated to be protective against ER stress-induced cell death. We hypothesized that exendin-4 (GLP-1 analog) treatment of fat loaded hepatocytes can reduce steatosis by autophagy which leads to reduced ER stress-related hepatocyte apoptosis.. Primary human hepatocytes were loaded with saturated, cis- and trans-unsaturated fatty acids (palmitic, oleic and elaidic acid respectively). Steatosis, induced with all three fatty acids, was significantly resolved after exendin-4 treatment. Exendin-4 sustained levels of GRP78 expression in fat-loaded cells when compared to untreated fat-loaded cells alone. In contrast, CHOP (C/EBP homologous protein); the penultimate protein that leads to ER stress-related cell death was significantly decreased by exendin-4 in hepatocytes loaded with fatty acids. Finally, exendin-4 in fat loaded hepatocytes clearly promoted gene products associated with macroautophagy as measured by enhanced production of both Beclin-1 and LC3B-II, markers for autophagy; and visualized by transmission electron microscopy (TEM). Similar observations were made in mouse liver lysates after mice were fed with high fat high fructose diet and treated with a long acting GLP-1 receptor agonist, liraglutide.. GLP-1 proteins appear to protect hepatocytes from fatty acid-related death by prohibition of a dysfunctional ER stress response; and reduce fatty acid accumulation, by activation of both macro-and chaperone-mediated autophagy. These findings provide a novel role for GLP-1 proteins in halting the progression of more aggressive lesions from underlying steatosis in humans afflicted with NAFLD.

Topics: Adipocytes; Animals; Apoptosis; Autophagy; Diet, High-Fat; Dietary Carbohydrates; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Exenatide; Fatty Liver; Fructose; Glucagon-Like Peptide 1; Hepatocytes; Humans; Life Style; Male; Mice; Mice, Inbred C57BL; Obesity; Peptides; Survival Analysis; Unfolded Protein Response; Venoms

Topics: Animals; Dietary Fats; Exenatide; Fatty Liver; Glucagon-Like Peptide-1 Receptor; Hepatocytes; Humans; Hypoglycemic Agents; Liver; Male; Non-alcoholic Fatty Liver Disease; Peptides; Receptors, Glucagon; Signal Transduction; Venoms

Glucagon-like peptide 1 (GLP-1) is a naturally occurring peptide secreted by the L cells of the small intestine. GLP-1 functions as an incretin and stimulates glucose-mediated insulin production by pancreatic beta cells. In this study, we demonstrate that exendin-4/GLP-1 has a cognate receptor on human hepatocytes and that exendin-4 has a direct effect on the reduction of hepatic steatosis in the absence of insulin. Both glucagon-like peptide 1 receptor (GLP/R) messenger RNA and protein were detected on primary human hepatocytes, and receptor was internalized in the presence of GLP-1. Exendin-4 increased the phosphorylation of 3-phosphoinositide-dependent kinase-1 (PDK-1), AKT, and protein kinase C zeta (PKC-zeta) in HepG2 and Huh7 cells. Small interfering RNA against GLP-1R abolished the effects on PDK-1 and PKC-zeta. Treatment with exendin-4 quantitatively reduced triglyceride stores compared with control-treated cells.. This is the first report that the G protein-coupled receptor GLP-1R is present on human hepatocytes. Furthermore, it appears that exendin-4 has the same beneficial effects in vitro as those seen in our previously published in vivo study in ob/ob mice, directly reducing hepatocyte steatosis. Future use for human nonalcoholic fatty liver disease, either in combination with dietary manipulation or other pharmacotherapy, may be a significant advance in treatment of this common form of liver disease.

Topics: 3-Phosphoinositide-Dependent Protein Kinases; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hepatocytes; Humans; Insulin; Peptides; Protein Kinase C; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Receptors, Glucagon; Signal Transduction; Venoms

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the Western world. The aim of this study was to evaluate the biochemical and histological effects of omega-3 fatty acid and exendin-4 treatment on NAFLD in an animal model.. Sixty-three 8-week-old outbred Sprague-Dawley male rats were used for this study. Three animals were used as procedure controls, and 30 rats were fed a methionine and choline deficient (MCD) diet and 30 were fed a regular chow diet. In each group of 30 animals, 10 served as controls, 10 received exendin-4, and 10 received omega-3 fatty acids. After 75 days of treatment, the animals were euthanized, the tissues and serum were harvested, and the livers were formalin-fixed for histology.. The MCD diet was exceptionally efficient at producing fatty livers. The MCD control animals had a liver steatosis score of 38+/-6.7 (of 50 possible); treatment with exendin-4 was not associated with a significant reduction of steatosis (44+/-5.16, P=0.07) and the omega-3 fatty acid treatment was associated with a significant decrease in the liver steatosis score (15.6+/-13.46, P<0.001) compared with both the controls and the exendin-4 groups. The omega-3 fatty acid treatment increased serum aspartate aminotransferase significantly, whereas exendin-4 had no effect.. In an animal model of NAFLD, the omega-3 fatty acid therapy was associated with significant improvement in hepatic steatosis compared with exendin-4. These data suggest that omega-3 fatty acid supplements may have a potential therapeutic role in patients with NAFLD.

Topics: Adipokines; Animals; Body Weight; Corn Oil; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP4A; Dietary Supplements; Disease Models, Animal; Exenatide; Fatty Acids, Omega-3; Fatty Liver; Fish Oils; Hypoglycemic Agents; Insulin Resistance; Liver; Male; Peptides; Rats; Rats, Sprague-Dawley; Venoms

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Exenatide; Fatty Liver; Female; Humans; Hypoglycemic Agents; Injections; Male; Middle Aged; Peptides; Prospective Studies; Treatment Outcome; Venoms

Topics: Antiviral Agents; Drug Therapy, Combination; Exenatide; Fatty Liver; Hepatitis C, Chronic; Humans; Hypoglycemic Agents; Interferon alpha-2; Interferon-alpha; Liver Function Tests; Male; Middle Aged; Peptides; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Ribavirin; Venoms; Viral Load

Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning problem in hepatology, and is associated with insulin resistance. Exendin-4 is a peptide agonist of the glucagon-like peptide (GLP) receptor that promotes insulin secretion. The aim of this study was to determine whether administration of Exendin-4 would reverse hepatic steatosis in ob/ob mice. Ob/ob mice, or their lean littermates, were treated with Exendin-4 [10 microg/kg or 20 microg/kg] for 60 days. Serum was collected for measurement of insulin, adiponectin, fasting glucose, lipids, and aminotransferase concentrations. Liver tissue was procured for histological examination, real-time RT-PCR analysis and assay for oxidative stress. Rat hepatocytes were isolated and treated with GLP-1. Ob/ob mice sustained a reduction in the net weight gained during Exendin-4 treatment. Serum glucose and hepatic steatosis was significantly reduced in Exendin-4 treated ob/ob mice. Exendin-4 improved insulin sensitivity in ob/ob mice, as calculated by the homeostasis model assessment. The measurement of thiobarbituric reactive substances as a marker of oxidative stress was significantly reduced in ob/ob-treated mice with Exendin-4. Finally, GLP-1-treated hepatocytes resulted in a significant increase in cAMP production as well as reduction in mRNA expression of stearoyl-CoA desaturase 1 and genes associated with fatty acid synthesis; the converse was true for genes associated with fatty acid oxidation. In conclusion, Exendin-4 appears to effectively reverse hepatic steatosis in ob/ob mice by improving insulin sensitivity. Our data suggest that GLP-1 proteins in liver have a novel direct effect on hepatocyte fat metabolism.

Topics: Adipose Tissue; Alanine Transaminase; Animals; Blood Glucose; Cyclic AMP; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Insulin Resistance; Lipid Peroxidation; Liver; Male; Mice; Mice, Obese; Peptides; PPAR alpha; Receptors, Glucagon; RNA, Messenger; Stearoyl-CoA Desaturase; Sterol Regulatory Element Binding Protein 1; Venoms; Weight Gain

Fat accumulation in the liver or non-alcoholic fatty liver disease (NAFLD) is regarded as a key pathogenic factor and component of the metabolic syndrome. It was reported that administration of the incretin mimetic exenatide reversed hepatic steatosis in an obese mouse model. We had the opportunity to study the effect of additional exenatide administration on liver fat content in a patient with type 2 diabetes.. A 59-year-old male with poorly controlled type 2 diabetes was treated with exenatide in addition to metformin monotherapy. Following 44 weeks of exenatide therapy, mean the liver fat measured by liver spectroscopy declined from 15.8% to 4.3%. This dramatic decrease in liver fat was accompanied by significant beneficial changes in several cardiovascular disease risk factors and improvement of all liver enzymes, in particular alanine aminotransferase, the most important marker of liver steatosis.. This case report suggests that the incretin mimetic exenatide decreases hepatic fat accumulation and may play a role in the future treatment of NAFLD, and the associated insulin resistance and cardiovascular risk factors in an ever-growing high-risk population.

Topics: Diabetes Mellitus, Type 2; Exenatide; Fatty Liver; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Peptides; Venoms