Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis (original) (raw)
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Hepatology, 2006
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 μg/kg or 20 μg/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.
Current Issues in Molecular Biology
Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been shown to improve glucose and lipid homeostasis, promote weight loss, and reduce cardiovascular risk factors. They are a promising therapeutic option for non-alcoholic fatty liver disease (NAFLD), the most common liver disease, associated with T2DM, obesity, and metabolic syndrome. GLP-1RAs have been approved for the treatment of T2DM and obesity, but not for NAFLD. Most recent clinical trials have suggested the importance of early pharmacologic intervention with GLP-1RAs in alleviating and limiting NAFLD, as well as highlighting the relative scarcity of in vitro studies on semaglutide, indicating the need for further research. However, extra-hepatic factors contribute to the GLP-1RA results of in vivo studies. Cell culture models of NAFLD can be helpful in eliminating extrahepatic effects on the alleviation of hepatic steatosis, modulation of lipid metabolism pathways, reduction of inflammation, and prevention of the pro...
Coagonist of GLP-1 and glucagon receptors ameliorates non-alcoholic fatty liver disease
Canadian journal of physiology and pharmacology, 2018
Nonalcoholic fatty liver disease (NAFLD) is often associated with obesity and type 2 diabetes. Coagonist of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) are under clinical investigation for the treatment of obesity and type 2 diabetes. In this study, we have demonstrated the effect of a balanced coagonist in the treatment of NAFLD using mice models. GLP-1R agonist exendin-4, glucagon, and coagonist (Aib2 C24 Chimera2) were administered to C57BL6/J mice, in which NAFLD was induced by carbon tetrachloride (CCl4) treatment after in high fat diet (HFD) feeding, and CDAHFD (choline-deficient, L-amino acid-defined, HFD). Repeated dose administration of coagonist significantly attenuated liver inflammation and steatosis induced by acute and long-term treatment with CCl4 in HFD-fed mice. Coagonist markedly attenuated the CDAHFD-induced expression of TIMP-1, MMP-9, TNF-α, MCP-1, COL1A1 and α-SMA. It also inhibited progression of hepatic steatosis and fibrosis in mic...
Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase
Journal of Hepatology, 2011
Background & Aims: Glucagon-like peptide-1 (GLP-1), a gutderived peptide degraded by dipeptidyl peptidase-4 (DPP4), stimulates insulin secretion in response to nutrients, yet its direct effect on the liver is controversial. We investigated the effects of GLP-1 on hepatic fat and glucose metabolism and elucidated its mechanism of action. Methods: Hepatic fat metabolism, including lipogenic enzymes and signal transduction regulators, was assessed in livers of DPP4-deficient rats (DPP4-) with chronically elevated GLP-1 and in GLP-1-treated primary hepatocytes. The effect of chronic elevated GLP-1 on insulin sensitivity was measured using the hyperinsulinemic-euglycemic clamp. Results: Normal and high fat diet fed DPP4-rats displayed reduced hepatic triglycerides, accompanied by down-regulation of lipogenesis enzymes and parallel up-regulation of carnitine palmitoyltransferase-1, a key enzyme in fatty acid b-oxidation. In vitro studies demonstrated that these effects were directly induced by GLP-1. Mechanistically, GLP-1 increased cAMP in hepatocytes, resulting in the phosphorylation of cAMP-activated protein kinase (AMPK), a suppressor of lipogenesis. Indeed, hepatocytes expressing a dominant negative Ad-DN-AMPK displayed attenuated GLP-1 effects on AMPK phosphorylation and its downstream lipogenic targets. Importantly, normoglycemic DPP4-rats did not display improved hepatic insulin sensitivity in vivo, suggesting a direct effect of GLP-1 on fat metabolism. Finally, DPP4-rats expressed lower levels of hepatic proinflammatory and profibrotic cytokines in response to nutrient stimuli. Conclusions: GLP-1 suppresses hepatic lipogenesis via activation of the AMPK pathway. GLP-1 inhibitory effects on hepatic fat accumulation and nutrient-induced hepatic proinflammatory response suggest GLP-1 analogs as novel therapies for nonalcoholic fatty liver diseases.
Efficacy of Glucagon-Like Peptide-1 Analogs in Nonalcoholic Fatty Liver Disease: A Systematic Review
Hepatic Medicine: Evidence and Research
Background: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. It is believed to be the hepatic manifestation of the metabolic syndrome. Many treatment approaches have been suggested so far, and several types of studies have been done to find treatment for NAFLD, the most promising of which are those with lifestyle interventions. Objective: The aim of this systematic review was to evaluate the efficacy and safety of glucagon-like peptide-1 (GLP-1) analogs on the management of NAFLD. Methods: The PubMed, MEDLINE, and Cochrane Central Library were searched to identify randomized controlled trials, single arm trials, and cohorts that compared GLP-1 analogs with a control treatment or baseline values with respect to efficacy and safety in patients living with NAFLD. The key outcomes were a change in serum transaminase, resolution of disease status measured by imaging or histological techniques, improvement in insulin resistance, and reduction in body weight. Results: Initial searching retrieved 201 peer-reviewed articles and abstracts. Ten studies met all inclusion criteria. The review included a total of 590 participants with NAFLD. Following administration of GLP-1 analogs, a decrease in serum transaminases, improvement in liver histology and insulin resistance, and a reduction in body weight were observed. Compared with baseline, body weight, alanine aminotransferase, aspartate aminotransferase, and gamma glutamyltransferase were decreased by 5.5%, 59.5%, 52.8%, and 44.8%, respectively, due to GLP-1. Likewise, a reduction of proinflammatory cytokines and fibrosis markers and an enhancement of protective adipokines were observed in some of the studies. Conclusion: The decrease in a key biochemical marker of liver injury following treatment with GLP-1 analogs, as well as improvements in imaging and histology, suggests that these agents may be effective alternatives for managing NAFLD. Registration: CRD42018087262.
Exenatide improves hepatic steatosis by enhancing lipid use in adipose tissue in nondiabetic rats
World journal of gastroenterology : WJG, 2014
To investigate the metabolic changes in skeletal muscle and/or adipose tissue in glucagon-like peptide-1-induced improvement of nonalcoholic fatty liver disease (NAFLD). Male Wistar rats were fed either a control diet (control group) or a high-fat diet (HFD). After 4 wk, the HFD-fed rats were subdivided into two groups; one group was injected with exenatide [HFD-Ex(+) group] and the other with saline [HFD-Ex(-) group] every day for 12 wk. The control group received saline and were fed a control diet. Changes in weight gain, energy intake, and oxygen consumption were analyzed. Glucose tolerance tests were performed after 8 wk of treatment. Histological assessments were performed in liver and adipose tissue. RNA expression levels of lipid metabolism related genes were evaluated in liver, skeletal muscle, and adipose tissue. Exenatide attenuated weight gain [HFD-Ex(-) vs HFD-Ex(+)] and reduced energy intake, which was accompanied by an increase in oxygen consumption and a decrease in t...