lignans and Non-alcoholic-Fatty-Liver-Disease

Dietary phytoestrogens are bioactive compounds with estrogenic activity. With the growing popularity of plant-based diets, the intake of phytoestrogen-rich legumes (especially soy) and legume-derived foods has increased. Evidence from preclinical studies suggests these compounds may have an effect on hormones and health, although the results of human trials are unclear. The effects of dietary phytoestrogens depend on the exposure (phytoestrogen type, matrix, concentration, and bioavailability), ethnicity, hormone levels (related to age, sex, and physiological condition), and health status of the consumer. In this review, we have summarized the results of human studies on dietary phytoestrogens with the aim of assessing the possible hormone-dependent outcomes and health effects of their consumption throughout a lifespan, focusing on pregnancy, childhood, adulthood, and the premenopausal and postmenopausal stages. In pregnant women, an improvement of insulin metabolism has been reported in only one study. Sex hormone alterations have been found in the late stages of childhood, and goitrogenic effects in children with hypothyroidism. In premenopausal and postmenopausal women, the reported impacts on hormones are inconsistent, although beneficial goitrogenic effects and improved glycemic control and cardiovascular risk markers have been described in postmenopausal individuals. In adult men, different authors report goitrogenic effects and a reduction of insulin in non-alcoholic fatty liver patients. Further carefully designed studies are warranted to better elucidate the impact of phytoestrogen consumption on the endocrine system at different life stages.

Topics: Adult; Child; Diet; Female; Glycine max; Gonadal Steroid Hormones; Heart Disease Risk Factors; Hormones; Humans; Hypothyroidism; Isoflavones; Lignans; Longevity; Male; Non-alcoholic Fatty Liver Disease; Phytoestrogens; Postmenopause; Pregnancy; Premenopause; Vegetables

Topics: Animals; Cyclooctanes; Humans; Lignans; Models, Biological; Non-alcoholic Fatty Liver Disease; Polycyclic Compounds; Protective Agents

Schisandra chinensis fruit is a well-known traditional Chinese medicine (TCM) that has been used to treat various liver diseases. Our previous study revealed that its extract is effective against nonalcoholic fatty liver disease (NAFLD).. This study aimed to elucidate the active components and explore the underlying mechanisms of action of S. chinensis fruit in the treatment of NAFLD.. A HepG2 cell model was used to screen the anti-NAFLD activity of the fraction from S. chinensis fruit extract. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to determine the components of the active fraction. Active compounds, potential targets, and key pathways were predicted for the active fraction treatment of NAFLD using network pharmacology. The anti-NAFLD effects of the active fraction and core active compound 3 were further validated using a high-fat diet (HFD)-induced NAFLD mouse model, intraperitoneal glucose tolerance test (IPGTT), and intraperitoneal insulin tolerance test (IPITT). Related hepatic mRNA expression was detected using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to preliminarily validate the mechanism.. In vitro experiments showed that the active fraction of S. chinensis fruit ethanol (EtOH) extract was mainly concentrated in the soluble fraction of petroleum ether (PET). Thirty-seven lignans were identified in this active fraction using UPLC-Q-TOF/MS. Network pharmacology studies have indicated that its anti-NAFLD effects lie in three major active lignans (3, 24, and 27) contained in PET, which may regulate the insulin resistance signaling pathway. In vivo experiments demonstrated that PET and core active compound 3 treatment significantly attenuated hepatic steatosis and reduced the levels of serum alanine transaminase (ALT), aspartate transaminase (AST), insulin, malondialdehyde (MDA), hepatic triglyceride (TG), and total cholesterol (TC) in HFD-induced mice (P < 0.05). Moreover, treatment with PET and compound 3 alleviated glucose tolerance and insulin resistance. These beneficial effects can be achieved by regulating the expression of Pik3ca, Gsk3β, Jnk1, and Tnf-α.. This study identified the main active fraction and compounds responsible for the anti-NAFLD activity of S. chinensis fruit. This mechanism may be related to regulation of the resistance pathway.

Topics: Animals; Fruit; Insulin; Insulin Resistance; Lignans; Mice; Network Pharmacology; Non-alcoholic Fatty Liver Disease; Plant Extracts; Schisandra; Technology

This study explored the effects of sesamin on nonalcoholic steatohepatitis (NASH). High-fat and high-fructose diet-fed mice supplemented with or without sesamin. The results suggested that sesamin-treated mice lost body weight and fat tissue weight, had lower levels of serum metabolic parameters, and insulin resistance was mitigated. Histological examinations showed that sesamin treatment mitigated the progression of hepatic steatosis, and inflammation. In addition, sesamin enhanced hepatic antioxidant capacity, and decreased the activations of hepatic c-jun N-terminal kinase, inhibitor of kappa B kinase α, and insulin receptor substrate 1 as well as hepatic interleukin-6 and tumor necrosis factor-alpha levels. Further experiments indicated that sesamin treatment downregulated GRP78 and phospho-inositol-requiring enzyme 1 (IRE1) expression, and upregulated x-box binding protein 1 (XBP1) expression in hepatic tissue. The aforementioned results suggest that sesamin alleviates obesity-associated NASH, which might be linked to the effect of sesamin on the regulation of the hepatic endoplasmic reticulum stress-IRE1/XBP1 pathway. Thus, sesamin may be a good food functional ingredient in the treatment of obesity-associated NASH.

Topics: Animals; Diet; Diet, High-Fat; Dioxoles; Fructose; Lignans; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Protein Serine-Threonine Kinases

Schisandra chinensis, a traditional Chinese medicinal herb, is rich in chemical constituents, including lignans, triterpenes, polysaccharides, and volatile oils. Clinically, it is commonly used to treat cardiovascular, cerebrovascular, liver, gastrointestinal, and respiratory diseases. Modern pharmacological studies have shown that S. chinensis extract and monomers have multiple pharmacological activities in lowering liver fat, alleviating insulin resistance, and resisting oxidative stress, and have good application prospects in alleviating nonalcoholic fatty liver disease(NAFLD). Therefore, this study reviewed the research progress on chemical constituents of S. chinensis and its effect on NAFLD in recent years to provide references for the research on S. chinensis in the treatment of NAFLD.

Topics: Insulin Resistance; Lignans; Non-alcoholic Fatty Liver Disease; Schisandra

Topics: AMP-Activated Protein Kinases; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Estrogen Receptor alpha; Hep G2 Cells; Humans; Lignans; Lipid Metabolism; Liver; Molecular Docking Simulation; Non-alcoholic Fatty Liver Disease; Palmitates; Signal Transduction; Sterol Regulatory Element Binding Protein 1

Type 2 diabetes mellitus (T2DM) is a metabolic risk factor associated with non-alcoholic liver disease (NAFLD). Schisandrin B (Sch B) is a promising agent for NAFLD. However, the actions of Sch B on diabetes-associated NAFLD and the underlying mechanisms are not characterized. This study aimed to assess whether Sch B has beneficial effects on T2DM-associated NAFLD. Sch B (50 mg/kg, gavage) was administrated to C57BL/KSJ db/db mice for 2 weeks. Body weight, liver weight, blood glucose, and insulin resistance were measured. Serum lipid level and liver function were detected using the biochemistry analyzer. Quantitative Real-Time PCR assay was used to evaluate mRNA levers of lipid metabolism genes. Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) staining was performed to measure apoptosis in the liver. Pathological analysis and immunohistochemistry assessment were used to analyze hepatic steatosis and inflammatory infiltration. Sch B supplementation significantly decrease body weight, related liver weight, blood glucose, and serum insulin, and improved insulin resistance in db/db mice. Sch B obviously corrected NAFLD phenotypes including lipid deposition, steatohepatitis, and high levels of hepatic enzymes and serum lipid. In addition, mRNA levels of Sterol response element-bind protein 1c (SREBP-1c), fatty acid synthetase (Fasn), and acetyl-CoA carboxylase (ACC) were markedly downregulated by Sch B treatment. TUNEL-positive cells were also decreased by Sch B. Furthermore, Sch B inhibited the Kupffer cells, IL-1β, and TNF-α infiltration to the liver. Sch B ameliorated insulin resistance and lipid accumulation under high glucose conditions, which was partly associated with its inhibition of apoptosis and anti-inflammatory actions.

Topics: Animals; Anti-Inflammatory Agents; Blood Glucose; Body Weight; Cyclooctanes; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Insulin Resistance; Lignans; Lipid Metabolism; Lipids; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Polycyclic Compounds; RNA, Messenger; Sterol Regulatory Element Binding Protein 1

Non-alcoholic fatty liver disease (NAFLD) can be attributed to the imbalance between lipogenesis and lipidolysis in the liver. Sesame lignans (sesamin, sesamolin, and sesamol) are unique bioactive compounds responsible for the nutritional function of sesame oils. However, the preventive effects of three lignans on oxidative stress and lipid metabolism in steatosis HepG2 cells have not been compared. In this study, we investigated the role of sesamin, sesamolin, and sesamol on hepatic lipid accumulation and explored the underlying mechanism via a well-established cell model. The results showed that 3 μg/ml of lignans could decrease the TG/TC contents and alleviate cellular oxidative stress, with an order of the lipid-lowering effect as sesamol > sesamin > sesamolin. The lignan-activated AMPK and PPAR signaling pathways enhanced gene and protein expressions related to fatty acid oxidation, cholesterol efflux, and catabolism. Meanwhile, treatment of the steatosis HepG2 cells with sesamin, sesamolin, and sesamol reduced lipid synthesis and cholesterol uptake, thus lowering intracellular lipogenesis in the process of NAFLD. Our data suggested that sesame lignans can attenuate oxidative stress and regulate lipid metabolism in liver cells, which may be potential therapeutic agents for treating the NAFLD. PRACTICAL APPLICATIONS: The present work demonstrated that sesame lignans can be used for dietary supplements or functional additives with excellent lipid-lowering effects. Furthermore, this study supplied potential molecular mechanisms involved in NAFLD treatment process, and also provided nutritional guidelines for sesame oil evaluation and selection.

Topics: Benzodioxoles; Cholesterol; Dioxoles; Hep G2 Cells; Humans; Lignans; Lipid Metabolism; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Phenols; Sesame Oil; Sesamum

Schisandrin B (Sch B), which inhibits hepatic steatosis caused by non-alcoholic fatty liver disease (NAFLD), is one of the most active dibenzocyclooctadienes isolated from Schisandra chinensis (Turcz.) Baill with various pharmacological activities. In this study, the role of Sch B-induced autophagy in lipid-lowering activities of Sch B was examined and the underlying mechanisms were elucidated.. Free fatty acid (FFA)-stimulated HepG2 cells and mouse primary hepatocytes (MPHs) and high-fat diet (HFD)-fed mice were used as NAFLD models. The role of Sch B-induced autophagy in lipid-lowering effects of Sch B was assessed using ATG5/TFEB-deficient cells and 3-methyladenine (3-MA)-treated hepatocytes and mice.. Sch B simultaneously active autophagy through AMPK/mTOR pathway and decreased the number of lipid droplets in FFA-treated HepG2 cells and MPHs. Additionally, siATG5/siTFEB transfection or 3-MA treatment mitigated Sch B-induced autophagy and activation of fatty acid oxidation (FAO) and ketogenesis in FFA-treated HepG2 cells and MPHs. Sch B markedly decreased hepatic lipid content and activated the autophagy through AMPK/mTOR pathway in HFD-fed mice. However, the activities of Sch B were suppressed upon 3-MA treatment. Sch B upregulated the expression of key enzymes involved in FAO and ketogenesis, which was mitigated upon 3-MA treatment. Moreover, changes in hepatic lipid components and amino acids may be related to the Sch B-induced autophagy pathway.. These results suggested that Sch B inhibited hepatic steatosis and promoted FAO by activation of autophagy through AMPK/mTOR pathway. Our study provides novel insights into the hepatic lipophagic activity of Sch B and its potential application in the management of NAFLD.

Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Cyclooctanes; Diet, High-Fat; Fatty Acids, Nonesterified; Hepatocytes; Ketone Bodies; Lignans; Lipid Metabolism; Liver; Mice; Non-alcoholic Fatty Liver Disease; Polycyclic Compounds; Signal Transduction; TOR Serine-Threonine Kinases

Lipophagy is an autophagic process, which delivers the intracellular lipid droplets to the lysosomes for degradation. Recent studies revealed that the impairment of lysosomal biogenesis and autophagic flux led to dysregulation of lipophagy in hepatocytes, which exacerbated the development of nonalcoholic fatty liver disease (NAFLD). Therefore, agents restoring autophagic flux and lipophagy in hepatocytes may have therapeutic potential against this increasingly prevalent disease. Phillygenin (PHI), a lignin extracted from Forsythia suspense, exerts hepatoprotective and anti-inflammatory effects. However, the effect of PHI on NAFLD remains unknown.. This study aimed to investigate the protective effect of PHI on NAFLD and elucidate the underlying mechanism.. The effects of PHI were examined in palmitate (PA)-stimulated AML12 cells and primary hepatocytes, as well as in NAFLD mice induced by a high-fat diet (HFD). We also used transcription factor EB (TFEB) knockdown hepatocytes and hepatocyte-specific TFEB knockout (TFEB. Our results indicated that autophagic flux and lysosome biogenesis in PA-stimulated hepatocytes were impaired. PHI alleviated lipid deposition by increasing lysosomal biogenesis and autophagic flux. It also stimulated the release of endoplasmic reticulum Ca. Despite PHI has been reported to have anti-hepatic fibrosis effects, whether it has a hepatoprotective effects against NAFLD and the underlying molecular mechanism remain unclear. Herein, we found that PHI restored lipophagy and suppressed lipid accumulation and inflammation by regulating the Ca

Topics: Animals; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Calcineurin; Hepatocytes; Inflammation; Lignans; Lipids; Lysosomes; Mice; Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is intricately linked to dysregulation of the gut-liver axis, and correlated with intestinal inflammation and barrier disruption.. To investigate the protective effects and possible molecular mechanism of Schisantherin A (Sin A) in a high-fat diet (HFD) induced NAFLD mouse model.. HFD-fed NAFLD mice were treated with the vehicle and 80 mg/kg Sin A every day for 6 weeks. The gut permeability of the NAFLD mice was assessed by intestinal permeability assays. We found that Sin A potently ameliorated HFD-induced hepatic steatosis and inflammation, alleviated gut inflammation, and restored intestinal barrier function. We also observed that Sin A improved gut permeability and reduced the release of lipopolysaccharide (LPS) into circulation and further found that Sin A can suppress LPS-TLR4 signaling to protect against HFD-induced NAFLD. Sin A treatment altered the composition of the microbiome in NAFLD mice compared to vehicle controls.. Sin A is an effective and safe hepatoprotective agent against HFD-induced NAFLD by partly ameliorating gut inflammation, restoring intestinal barrier function, and regulating intestinal microbiota composition.

Topics: Animals; Anti-Bacterial Agents; Cyclooctanes; Dioxoles; Inflammation; Lignans; Lipopolysaccharides; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; RNA, Ribosomal, 16S; Toll-Like Receptor 4

The liver X receptors (LXRs) are major regulators of lipogenesis, and their reduced activation by an inhibitor could be a treatment strategy for fatty liver disease. Small molecules originating from dietary food are considered suitable and attractive drug candidates for humans in terms of safety. In this study, an edible plant,

Topics: Acetyl-CoA Carboxylase; Animals; Benzofurans; Diet, High-Fat; Fatty Acid Synthases; Furans; Humans; Lignans; Lipogenesis; Liver; Liver X Receptors; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Plant Extracts; Primulaceae; Sterol Regulatory Element Binding Protein 1; Triglycerides

We hypothesized that schizandrin (SCH) A, a lignan found in the fruits of the Schisandra genus, would exert protective effects against high-fat and high-cholesterol (HFHC) diet-induced nonalcoholic fatty liver disease (NAFLD) via regulation of lipid metabolism and oxidative stress. To test our hypothesis, male C57BL/6J mice were fed an HFHC diet with or without SCH A for 15 weeks. There were no significant differences in food intake, body weight, fat mass, and plasma total cholesterol level between the 2 groups. However, supplementation of SCH A significantly decreased levels of plasma free fatty acid and triglyceride, whereas plasma high-density lipoprotein cholesterol level was increased in the SCH A-supplemented mice. Moreover, hepatic free fatty acid, triglyceride, and cholesterol content, as well as hepatic lipid droplet accumulation, were markedly lower in the SCH A group in contrast to the control group. Activity of hepatic enzymes involved in fatty acid and triglyceride synthesis was significantly decreased by SCH A supplementation, whereas SCH A markedly increased hepatic β-oxidation and fatty acid oxidation-related gene expression as well as fecal excretion of free fatty acid and triglyceride. SCH A also significantly increased expression of genes involved in cholesterol homeostasis (biliary cholesterol excretion and cholesterol efflux to high-density lipoprotein) in the liver. Moreover, SCH A significantly decreased hepatic lipid peroxidation, which was accompanied by increased hepatic antioxidant enzymes activity. These results suggest that SCH A could alleviate HFHC diet-induced NAFLD by regulating hepatic lipid metabolism and oxidative stress as well as fecal lipid excretion.

Topics: Animals; Antioxidants; Cholesterol; Cholesterol, Dietary; Cholesterol, HDL; Cyclooctanes; Diet, High-Fat; Dietary Fats; Dietary Supplements; Fatty Acids; Fatty Acids, Nonesterified; Feces; Lignans; Lipid Metabolism; Liver; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Phytotherapy; Plant Extracts; Polycyclic Compounds; Schisandra; Triglycerides

Non-alcoholic steatohepatitis (NASH) may develop into hepatic cirrhosis. This study aimed to investigate whether honokiol could prevent NASH induced by high-cholesterol and high-fat (CL) diet in mice and the possible mechanism involved.. Mice were fed with CL diet for 12 weeks to establish a NASH model; honokiol (0.02% w/w in diet) was added to evaluate its effect on NASH. Murine peritoneal macrophages, RAW264.7 and ANA-1 cells, were used to explore the possible mechanisms of honokiol on macrophage polarization.. Mice developed NASH after fed with CL diet for 12 weeks. Honokiol supplementation alleviated insulin resistance, hepatic steatosis, inflammation, and fibrosis induced by CL diet. Immunohistochemistry showed that honokiol induced more M2 macrophages in livers compared with CL diet alone. Honokiol decreased M1 marker genes (TNFα and MCP-1) and increased M2 marker gene (YM-1, IL-10, IL-4R and IL-13) expression in mice liver compared with CL diet. Moreover, treatment with honokiol lowered alanine aminotransferase and aspartate aminotransferase in serum and preserved liver from lipid peroxidation, evidenced by lowered hepatic malondialdehyde level. Honokiol has antioxidant function, as honokiol upregulated hepatic glutathione and superoxide dismutase level and downregulated hepatic CYP2E1 protein level. Hepatic peroxisome proliferator-activated receptor γ (PPARγ) and its target genes were upregulated by honokiol. Furthermore, honokiol (10 μM) treatment in mouse peritoneal cells, RAW264.7 cells and ANA-1 cells, led to M2 macrophage polarization, whereas a PPARγ antagonist, GW9662, abolished this effect of honokiol.. Honokiol can attenuate CL diet-induced NASH and the mechanism in which possibly is polarizing macrophages to M2 phenotype via PPARγ activation.

Topics: Animals; Biphenyl Compounds; Cell Polarity; Diet, High-Fat; Lignans; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; PPAR gamma; RAW 264.7 Cells

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, and is associated with the development of metabolic syndrome. Postmenopausal women with estrogen deficiency are at a higher risk of progression to NAFLD. Estrogen has a protective effect against the progression of the disease. Currently, there are no safe and effective treatments for these liver diseases in postmenopausal women. Honokiol (Ho), a bioactive natural product derived from Magnolia spp, has anti-inflammatory, anti-angiogenic, and anti-oxidative properties. In our study, we investigated the beneficial effects of Ho on NAFLD in ovariectomized (OVX) mice. We divided the mice into four groups, as follows: SHAM, OVX, OVX+β-estradiol (0.4 mg/kg of bodyweight), and OVX+Ho (50 mg/kg of diet). Mice were fed diets with/without Ho for 12 weeks. The bodyweight, epidermal fat, and weights of liver tissue were lower in the OVX group than in the other groups. Ho improved hepatic steatosis and reduced proinflammatory cytokine levels. Moreover, Ho markedly downregulated plasma lipid levels. Our results indicate that Ho ameliorated OVX-induced fatty liver and inflammation, as well as associated lipid metabolism. These findings suggest that Ho may be hepatoprotective against NAFLD in postmenopausal women.

Topics: Adiposity; Animals; Biomarkers; Biphenyl Compounds; Body Weight; Cytokines; Disease Models, Animal; Fatty Liver; Gene Expression Profiling; Inflammation Mediators; Lignans; Lipid Metabolism; Liver; Mice; Non-alcoholic Fatty Liver Disease; Organ Size; Ovariectomy

Arctigenin (ATG), a lignin extracted from Arctium lappa (L.), exerts antioxidant and anti-inflammatory effects. We hypothesized that ATG exerts a protective effect on hepatocytes by preventing nonalcoholic fatty liver disease (NAFLD) progression associated with lipid oxidation-associated lipotoxicity and inflammation. We established an in vitro NAFLD cell model by using normal WRL68 hepatocytes to investigate oleic acid (OA) accumulation and the potential bioactive role of ATG. The results revealed that ATG inhibited OA-induced lipid accumulation, lipid peroxidation, and inflammation in WRL68 hepatocytes, as determined using Oil Red O staining, thiobarbituric acid reactive substance assay, and inflammation antibody array assays. Quantitative RT-PCR analysis demonstrated that ATG significantly mitigated the expression of acetylcoenzyme A carboxylase 1 and sterol regulatory element-binding protein-1 and significantly increased the expression of carnitine palmitoyltransferase 1 and peroxisome proliferator-activated receptor alpha. The 40 targets of the Human Inflammation Antibody Array indicated that ATG significantly inhibited the elevation of the U937 lymphocyte chemoattractant, ICAM-1, IL-1β, IL-6, IL-6sR, IL-7, and IL-8. ATG could activate the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and AMP-activated protein kinase (AMPK) pathways and could increase the phosphorylation levels of Akt and AMPK to mediate cell survival, lipid metabolism, oxidation stress, and inflammation. Thus, we demonstrated that ATG could inhibit NAFLD progression associated with lipid oxidation-associated lipotoxicity and inflammation, and we provided insights into the underlying mechanisms and revealed potential targets to enable a thorough understanding of NAFLD progression.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Arctium; Carnitine O-Palmitoyltransferase; Fatty Liver; Furans; Hep G2 Cells; Hepatocytes; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukins; Lignans; Liver; Non-alcoholic Fatty Liver Disease; Oleic Acid; Oxidative Stress; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phytotherapy; Plant Extracts; PPAR alpha; Proto-Oncogene Proteins c-akt; Signal Transduction; Sterol Regulatory Element Binding Protein 1

Nonalcoholic fatty liver disease (NAFLD) is defined by a nonalcohol relevant pathological accumulation of fat in the liver. Previous studies have shown that sesamin exerts antioxidant effects and improves lipid metabolism of the fatty liver. In this study, we hypothesized that sesamin improves lipid homeostasis of Sprague-Dawley rats fed a high-fat diet (HFD) by regulating the expression of genes related to de novo lipogenesis and β-oxidation. We induced NAFLD in rats with HFD and examined the effect of sesamin in vivo. The results showed that HFD rats accumulated total cholesterol and triacylglycerols in the liver and developed inflammation, as evidenced by the elevation of interleukin-6 and tumor necrosis factor-α in the liver and serum. Sesamin attenuated the disease progression by improving the blood lipid profile in a dose-dependent manner. Sesamin reduced the serum levels of total cholesterol, triacylglycerols, low-density lipoprotein cholesterol, and free fatty acid, whereas it increased the level of high-density lipoprotein cholesterol. Meanwhile, sesamin increased the activities of hepatic glutathione peroxidase and superoxide dismutase while reducing the level of malonaldehyde and cytochrome P450 2E1. Furthermore, higher doses of sesamin reduced the expression of liver X receptor α and its downstream target genes, whereas it upregulated the peroxisome proliferator-activated receptor α-mediated signaling. These findings suggest that sesamin attenuates diet-induced dyslipidemia and inflammation of NAFLD in rats via mechanisms regulated by liver X receptor α and peroxisome proliferator-activated receptor α.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cytochrome P-450 CYP2E1; Diet, High-Fat; Dioxoles; Dyslipidemias; Hypolipidemic Agents; Inflammation; Interleukin-6; Lignans; Lipid Metabolism; Lipids; Lipogenesis; Liver; Liver X Receptors; Male; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Phytotherapy; Plant Extracts; PPAR alpha; Rats, Sprague-Dawley; Sesamum; Tumor Necrosis Factor-alpha

Schisandrin B (SchB) is one of the most abundant bioactive dibenzocyclooctadiene derivatives found in the fruit of Schisandra chinensis. Here, we investigated the potential therapeutic effects of SchB on non-alcoholic fatty-liver disease (NAFLD). In lipidomic study, ingenuity pathway analysis highlighted palmitate biosynthesis metabolic pathway in the liver samples of SchB-treated high-fat-diet-fed mice. Further experiments showed that the SchB treatment reduced expression and activity of fatty acid synthase, expressions of hepatic mature sterol regulatory element binding protein-1 and tumor necrosis factor-α, and hepatic level of palmitic acid which is known to promote progression of steatosis to steatohepatitis. Furthermore, the treatment also reduced hepatic fibrosis, activated nuclear factor-erythroid-2-related factor-2 which is known to attenuate the progression of NASH-related fibrosis. Interestingly, in fasting mice, a single high-dose SchB induced transient lipolysis and increased the expressions of adipose triglyceride lipase and phospho-hormone sensitive lipase. The treatment also increased plasma cholesterol levels and 3-hydroxy-3-methylglutaryl-CoA reductase activity, reduced the hepatic low-density-lipoprotein receptor expression in these mice. Our data not only suggest SchB is a potential therapeutic agent for NAFLD, but also provided important information for a safe consumption of SchB because SchB overdosed under fasting condition will have adverse effects on lipid metabolism.

Topics: Animals; Cyclooctanes; Diet, High-Fat; Disease Models, Animal; Fasting; Fatty Acid Synthases; Fatty Acids; Lignans; Lipid Metabolism; Lipids; Lipolysis; Liver; Liver Cirrhosis; Male; Metabolic Networks and Pathways; Metabolomics; Mice; NF-E2-Related Factor 2; Non-alcoholic Fatty Liver Disease; Palmitic Acid; Polycyclic Compounds; Sterol Regulatory Element Binding Protein 1; Tumor Necrosis Factor-alpha

Collaborative regulation of liver X receptor (LXR) and sterol regulatory element binding protein (SREBP)-1 are main determinants in hepatic steatosis, as shown in both animal models and human patients. Recent studies indicate that selective intervention of overly functional LXRα in the liver shows promise in treatment of fatty liver disease. In the present study, we evaluated the effects of meso-dihydroguaiaretic acid (MDGA) on LXRα activation and its ability to attenuate fatty liver in mice. MDGA inhibited activation of the LXRα ligand-binding domain by competitively binding to the pocket for agonist T0901317 and decreased the luciferase activity in LXRE-tk-Luc-transfected cells. MDGA significantly attenuated hepatic neutral lipid accumulation in T0901317- and high fat diet (HFD)-induced fatty liver. The effect of MDGA was so potent that treatment with 1mg/kg for 2 weeks completely reversed the lipid accumulation induced by HFD feeding. MDGA reduced the expression of LXRα co-activator protein RIP140 and LXRα target gene products associated with lipogenesis in HFD-fed mice. These results demonstrate that MDGA has the potential to attenuate nonalcoholic steatosis mediated by selective inhibition of LXRα in the liver in mice.

Topics: Animals; Base Sequence; Cell Line, Tumor; Diet, High-Fat; DNA Primers; Fatty Liver; Guaiacol; Humans; Lignans; Lipogenesis; Liver X Receptors; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Non-alcoholic Fatty Liver Disease; Orphan Nuclear Receptors

Hepatic lipid accumulation is a major risk factor for dyslipidemia, nonalcoholic fatty liver disease, and insulin resistance. The present study was conducted to evaluate hypolipidemic effects of meso-dihydroguaiaretic acid (MDA), anti-oxidative and anti-inflammatory compound isolated from the Myristica fragrans HOUTT., by oil red O staining, reverse transcription-polymerase chain reaction (RT-PCR), and Western blot. MDA significantly inhibited insulin-induced hepatic lipid accumulation in a dose-dependent manner. The lipid-lowering effect of MDA was accompanied by increased expression of proteins involved in fatty acid oxidation and decreased expression of lipid synthetic proteins. In addition, MDA activated AMP-activated protein kinase (AMPK) as determined by phosphorylation of acetyl-CoA carboxylase (ACC), a downstream target of AMPK. The effects of MDA on lipogenic protein expression were suppressed by pretreatment with compound C, an AMPK inhibitor. Taken together, these findings show that MDA inhibits insulin-induced lipid accumulation in human HepG2 cells by suppressing expression of lipogenic proteins through AMPK signaling, suggesting a potent lipid-lowering agent.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Cell Culture Techniques; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Dyslipidemias; Enzyme Activation; Enzyme Inhibitors; Fatty Liver; Guaiacol; Hep G2 Cells; Humans; Hypolipidemic Agents; Insulin Resistance; Lignans; Lipid Metabolism; Liver; Molecular Targeted Therapy; Myristica; Non-alcoholic Fatty Liver Disease; Phosphorylation; Phytotherapy; Plant Extracts; Pyrazoles; Pyrimidines