GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway.

The incidence of nonalcoholic fatty liver disease (NAFLD) keeps rising year by year, and NAFLD is rapidly becoming the most common liver disease worldwide. Clinical studies have found that glucagon-like peptide-1 (GLP-1) analogue, liraglutide (LRG), cannot only reduce glucose levels, but also improve hepatic lipase, especially in patients also with type 2 diabetes mellitus (T2DM). In addition, enhancing autophagy decreases lipid accumulation in hepatocytes. The aim of the present study is to explore the effect of LRG on hepatocyte steatosis and the possible role of autophagy. We set up an obesity mouse model with a high-fat diet (HFD) and induced hepatocyte steatosis with free fatty acids (FFA) in human L-O2 cells. LRG and two inhibitors of autophagy, Chloroquine (CQ) and bafilomycin A1 (Baf), were added into each group, respectively. The lipid profiles and morphological modifications of each group were tested. Immunohistochemistry, immunofluorescence staining and transmission electron microscopy (TEM) were used to measure autophagy in this study. The autophagy protein expression of SQSTM1 (P62), and LC3B, along with the signaling pathway proteins of mTOR, phosphorylated mTOR (p-mTOR), AMPK, phosphorylated AMPK (p-AMPK) and Beclin1, were evaluated by western blot. Our results showed that LRG improved hepatocyte steatosis by inducing autophagy, and the AMPK/mTOR pathway is involved. These findings suggest an important mechanism for the positive effects of LRG on hepatic steatosis, and provide new evidence for clinical use of LRG in NAFLD.

He Q ，Sha S ，Sun L ，Zhang J ，Dong M ... -  《-》

LRG ameliorates steatohepatitis by activating the AMPK/mTOR/SREBP1 signaling pathway in C57BL/6J mice fed a high‑fat diet.

Hao T ，Chen H ，Wu S ，Tian H ... -  《-》

Acetaminophen aggravates fat accumulation in NAFLD by inhibiting autophagy via the AMPK/mTOR pathway.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease which affects millions of people worldwide. Acetaminophen (APAP) overdose is the leading cause of acute liver failure. In this study, APAP (50, 100, 200 mg/kg) were employed on mice fed with a high-fat diet, and APAP (2, 4, 8 mM) were cultured with L02 cells in the presence of alcohol and oleic acid. APAP treatment significantly aggravated hepatic lipid accumulation, increased the serum levels of triglyceride (TG), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and increased hepatic lipid accumulation in H&E and Oil red O staining results. Transmission electron microscopy (TEM) found fewer number of autophagosomes in APAP (100 mg/kg) treated group. Immunohistochemistry analysis showed the intensity of hepatic mTOR was increased and AMPK was decreased in 200 mg/kg APAP treated group. Western blot analysis showed APAP treatment decreased the levels of LC3-Ⅱ, Beclin1 and AMPK, while increased the levels of mTOR and SREBP-1c, respectively. In vitro study showed APAP treatment obviously increased TG activities in cell supernatant, and Oil red O staining had the same results. Western blot analysis demonstrated APAP treatment decreased the levels of LC3-Ⅱ, Beclin1 and AMPK, increased the levels of mTOR and SREBP-1c, but rapamycin treatment significantly reversed these effects of APAP. In conclusion, therapeutic dosages of APAP aggravates fat accumulation in NAFLD, the potential mechanism might be involved in inhibiting autophagy associated with the AMPK/mTOR pathway, and patients with NAFLD should use a lower dose of APAP.

Shi C ，Xue W ，Han B ，Yang F ，Yin Y ，Hu C ... -  《-》

[Liraglutide alleviates lipotoxic liver cell damage and promotes autophagy to improve non-alcoholic fatty liver].

Zhang Q ，Liu Q ，Niu CY 《-》

The preventive effect of liraglutide on the lipotoxic liver injury via increasing autophagy.

The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing. Previous studies indicated that Liraglutide, glucagon-like peptide-1 analogue, could regulate glucose homeostasis as a valuable treatment for Type 2 Diabetes. However, the precise effect of Liraglutide on NAFLD model in rats and the mechanism remains unknown. In this study, we investigated the molecular mechanism by which Liraglutide ameliorates hepatic steatosis in a high-fat diet (HFD)-induced rat model of NAFLD in vivo and in vitro. NALFD rat models and hepatocyte steatosis in HepG2 cells were induced by HFD and palmitate fatty acid treatment, respectively. AMPK inhibitor, Compound C was added in HepG2 cells. Autophagy-related proteins LC3, Beclin1 and Atg7, and AMPK pathway-associated proteins were evaluated by Western blot and RT-PCR. Liraglutide enhanced autophagy as showed by the increased expression of the autophagy markers LC3, Beclin1 and Atg7 in HFD rats and HepG2 cells treated with palmitate fatty acid. In vitro, The AMPK inhibitor exhibited an inhibitory effect on Liraglutide-induced autophagy enhancement with the deceased expression of LC3, Beclin1 and Atg7. Additionally, Liraglutide treatment elevated AMPK levels and TSC1, decreased p-mTOR expression. Liraglutide could upregulate autophagy to decrease lipid over-accumulation via the AMPK/mTOR pathway.

He Y ，Ao N ，Yang J ，Wang X ，Jin S ，Du J ... -  《Annals of Hepatology》