anandamide and Non-alcoholic-Fatty-Liver-Disease

Nonalcoholic fatty liver disease (NAFLD) is a very common disease, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and is considered the hepatic expression of metabolic syndrome. Liver biopsy is currently considered the gold standard in diagnosis of NAFLD; however, it is an invasive technique and carries many risks. The serum anandamide level is recently discovered to play an important role as the potential indicator for NAFLD severity. The purpose of the study is to determine the association of endocannabinoid metabolite anandamide and NAFLD severity and to investigate its association with anthropometric and metabolic features in NAFLD patients.. A case-control study on 36 NAFLD biopsy-proven NAFLD patients and 15 healthy volunteers. They were subjected to full clinical history and examination, laboratory tests, abdominal ultrasound and serological testing of anadamide.. The anadamide level was significantly higher among NAFLD subgroups (simple steatosis and NASH) vs. the normal group (1.1, 0.29 vs. 0.2 P value = 0.00085), with cutoff 0.58 in the NASH group (accuracy 89%; sensitivity 66% and specificity 100%) (P value < 0.01).. Anandamide could be a specific serum marker for NASH and can be used to detect NAFLD severity.

Topics: Arachidonic Acids; Case-Control Studies; Endocannabinoids; Humans; Liver; Non-alcoholic Fatty Liver Disease; Polyunsaturated Alkamides; Predictive Value of Tests

To evaluate the association between circulating levels of endocannabinoids (eCBs) and non-alcoholic fatty liver disease (NAFLD).. The serum levels of the main eCBs, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their endogenous precursor and breakdown product, arachidonic acid (AA), were analyzed by liquid chromatography/tandem mass spectrometry in 105 volunteers screened for NAFLD. Hepatic ultrasound, fasting blood tests, and anthropometrics were assessed. Liver fat was quantified by the hepato-renal-ultrasound index representing the ratio between the brightness level of the liver and the kidney.. Patients with NAFLD had higher levels (pmol/mL) of AA (2,721 ± 1,112 vs. 2,248 ± 977, P = 0.022) and 2-AG (46.5 ± 25.8 vs. 33.5 ± 13.6, P = 0.003), but not AEA. The trend for higher levels of AA and 2-AG in the presence of NAFLD was observed in both genders and within subgroups of overweight and obesity. The association of AA and 2-AG with NAFLD was maintained with adjustment for age, gender, and BMI (OR = 1.001, 1.000-1.001 95% CI, P = 0.008 and OR = 1.05, 1.01-1.09, P = 0.006, respectively) or waist circumference.. This study is the first to show high circulating levels of 2-AG and AA in NAFLD patients compared with controls, independent of obesity. The findings may suggest an independent role of eCBs in the pathogenesis of NAFLD.

Topics: Adult; Alanine Transaminase; Arachidonic Acids; Case-Control Studies; Endocannabinoids; Female; Glycerides; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Polyunsaturated Alkamides; Waist Circumference

The content of the marine n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is far lower in lean than in fatty seafood. Cod filets contain less than 2g fat per kg, whereof approximately 50% is EPA and DHA. However, a large fraction of these n-3 PUFAs is present in the phospholipid (PL) fraction and may have high bioavailability and capacity to change the endocannabinoid profile. Here we investigated whether exchanging meat from a lean terrestrial animal with cod in a background Western diet would alter the endocannabinoid tone in mice and thereby attenuate obesity development and hepatic lipid accumulation. Accordingly, we prepared iso-caloric diets with 15.1 energy (e) % protein, 39.1 e% fat and 45.8 e% carbohydrates using freeze-dried meat from cod filets or pork sirloins, and using a combination of soybean oil, corn oil, margarine, milk fat, and lard as the fat source. Compared with mice receiving diets containing pork, mice fed cod gained less adipose tissue mass and had a lower content of hepatic lipids. This was accompanied by a lower n-6 to n-3 ratio in liver PLs and in red blood cells (RBCs) in the mice. Furthermore, mice receiving the cod-containing diet had lower circulating levels of the two major endocannabinoids, N-arachidonoylethanolamine and 2-arachidonoylglycerol. Together, our data demonstrate that despite the relatively low content of n-3 PUFAs in cod fillets, the cod-containing diet could exert beneficial metabolic effects.

Topics: Algorithms; Animals; Arachidonic Acids; Diet, Western; Endocannabinoids; Erythrocytes; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Functional Food; Gadus morhua; Glycerides; Lipid Metabolism; Liver; Male; Meat; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Phospholipids; Polyunsaturated Alkamides; Seafood

Obesity-related insulin resistance contributes to cardiovascular disease. Cannabinoid receptor-1 (CB(1)) blockade improves insulin sensitivity in obese animals and people, suggesting endocannabinoid involvement. We explored the role of hepatic CB(1) in insulin resistance and inhibition of insulin signaling pathways.. Wild-type mice and mice with disruption of CB(1) (CB(1)(-/-) mice) or with hepatocyte-specific deletion or transgenic overexpression of CB(1) were maintained on regular chow or a high-fat diet (HFD) to induce obesity and insulin resistance. Hyperinsulinemic-euglycemic clamp analysis was used to analyze the role of the liver and hepatic CB(1) in HFD-induced insulin resistance. The cellular mechanisms of insulin resistance were analyzed in mouse and human isolated hepatocytes using small interfering or short hairpin RNAs and lentiviral knockdown of gene expression.. The HFD induced hepatic insulin resistance in wild-type mice, but not in CB(1)(-/-) mice or mice with hepatocyte-specific deletion of CB(1). CB(1)(-/-) mice that overexpressed CB(1) specifically in hepatocytes became hyperinsulinemic as a result of reduced insulin clearance due to down-regulation of the insulin-degrading enzyme. However, they had increased hepatic glucose production due to increased glycogenolysis, indicating hepatic insulin resistance; this was further increased by the HFD. In mice with hepatocytes that express CB(1), the HFD or CB(1) activation induced the endoplasmic reticulum stress response via activation of the Bip-PERK-eIF2α protein translation pathway. In hepatocytes isolated from human or mouse liver, CB(1) activation caused endoplasmic reticulum stress-dependent suppression of insulin-induced phosphorylation of akt-2 via phosphorylation of IRS1 at serine-307 and by inducing the expression of the serine and threonine phosphatase Phlpp1. Expression of CB(1) was up-regulated in samples from patients with nonalcoholic fatty liver disease.. Endocannabinoids contribute to diet-induced insulin resistance in mice via hepatic CB(1)-mediated inhibition of insulin signaling and clearance.

Topics: Animals; Arachidonic Acids; Diet, High-Fat; Endocannabinoids; Endoplasmic Reticulum Stress; Fatty Liver; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Liver; Male; Metabolic Clearance Rate; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Phosphorylation; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-akt; Receptor, Cannabinoid, CB1; Signal Transduction