Liraglutide Attenuates Nonalcoholic Fatty Liver Disease through Adjusting Lipid Metabolism via SHP1/AMPK Signaling Pathway

Abstract

A glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide (LR) had been experimentally and clinically shown to ameliorate nonalcoholic fatty liver disease (NAFLD). This study aimed to investigate the beneficial effect of LR on NAFLD in vivo and in vitro and its underlying molecular mechanism. The effects of LR were examined on the high-fat diet-induced in vivo model in mice and in vitro model of NAFLD in human HepG2 cells. Liver tissues and HepG2 cells were procured for measuring lipid metabolism, histological examination, and western blot analysis. LR administration significantly lowered the serum lipid profile and lipid disposition in vitro and in vivo because of the altered expression of enzymes on hepatic gluconeogenesis and lipid metabolism. Moreover, LR significantly decreased Src homology region 2 domain-containing phosphatase-1 (SHP1) and then increased the expression of phosphorylated-AMP-activated protein kinase (p-AMPK). However, the overexpression of SHP1 mediated by lentivirus vector reversed LR-induced improvement in lipid deposition. Moreover, SHP1 silencing could further increase the expression of p-AMPK to ameliorate lipid metabolism and relative lipogenic gene induced by LR. In addition, abrogation of AMPK by Compound C eliminated the protective effects of LR on lipid metabolism without changing the expression of SHP1. LR markedly prevented NAFLD through adjusting lipid metabolism via SHP1/AMPK signaling pathway.

Protective Effect of a Mixture of Astragalus membranaceus and Lithospermum erythrorhizon Extract against Hepatic Steatosis in High Fat Diet‐Induced Nonalcoholic Fatty Liver Disease Mice

“…In the liver, SREBP-1c is an important transcription factor regulating fatty acid, cholesterol, and TG synthesis, and FAS is involved in lipid accumulation [57]. Previous studies have reported that downregulation of SREBP-1c and FAS, by the increased activation of AMPK, decreases lipid accumulation, and deposition, thereby improving hepatic steatosis [58,59]. Our results showed that ALM16 reversed the HFD-induced downregulation of CPT-1, involved in fatty acid oxidation, in the HFD-fed mice.…”

Cacao polyphenols regulate the circadian clock gene expression and through glucagon-like peptide-1 secretion

“…This finding supports previous one that an agonist of GLP-1 receptor liraglutide promoted AMPK phosphorylation in the liver. ( 39 ) AMPK is an important regulator of metabolism and circadian rhythm. ( 40 ) It is reported that AMPK regulates the expression of several clock gene products in mammalian tissues, because AMPK phosphorylates CRY1 and CRY2 and stimulates their degradation.…”

Fatty liver disease and primary liver cancer: disease mechanisms, emerging therapies and the role of bariatric surgery

“…Liraglutide, an antidiabetic GLP-1 agonist, in a phase 2 clinical trial, resulted in histological resolution of NASH in 39% of patients, compared with only 9% of patients treated with placebo [35]. More recent studies, in several different countries, have found similar results [36][37][38][39]. Pioglitazone, a PPARγ agonist, improved NASH histology both in patients with prediabetics and with type 2 diabetes, with a greater improvement in fibrosis in those with type 2 diabetes [40], and is endorsed by multiple international societies for the treatment of patients with NAFLD [41][42][43][44].…”

“…The molecular underpinnings of the evolution from NAFLD to NASH to liver cancer (with or without cirrhosis) are well understood [5,19,52], and multiple studies are underway targeting specific parts of this progression [30,[36][37][38][39]53]. NAFLD and NASH typically occur in patients with metabolic syndrome.…”