GLP-1 analogue prevents NAFLD in ApoE KO mice with diet and Acrp30 knockdown by inhibiting c-JNK.

Liraglutide, a Glucagon-like peptide-1(GLP-1) analogue with 97% sequence identity to human GLP-1, increases insulin secretion and insulin sensitivity. Its effect on non-alcoholic fatty liver disease (NAFLD) remains poorly understood. In this study, we examined whether liraglutide can protect against inflammatory stress by inhibiting activation of c-Jun N-terminal protein kinase (JNK). ApoE KO and adiponectin (Acrp30) knockdown mice fed a high-fat diet (HFD) were treated with liraglutide (1 mg/kg, twice daily) for 8 weeks. Liver tissue was procured for histological examination, real-time RT-PCR and Western blot analysis. The results showed that the combination of HFD, Acrp30 knockdown and ApoE deficiency had additive effects on the development of insulin resistance (IR) and NAFLD. Administration of liraglutide prevented the development of HFD and hypoadiponectinaemia-induced IR and NAFLD in this model. Liraglutide also attenuated the expression of proinflammatory cytokines or transcription factor, including TNF-α and NF-κB(65) , and the expression of two lipogenesis-related genes, Acetyl-CoA Carboxylase (ACC) and fatty acid synthase (FAS). These changes were accompanied by elevated plasma of Acrp30, increased Acrp30 mRNA, AMP Kinase phosphorylation, and decreased mitogen-activated protein kinase 4 (MKK4) mRNA expression and JNK phosphorylation. Our study also showed potent inhibitory effects of liraglutide on MKK4/JNK signalling which may be a mechanism for the observed improved insulin sensitivity and inflammatory stress induced by HFD and hypoadiponectinaemia.

Zhang L ，Yang M ，Ren H ，Hu H ，Boden G ，Li L ，Yang G ... -  《-》

[Liraglutide protects against nonalcoholic fatty liver disease in ApoE knockout mice with high-fat diet and silenced Acrp30 by increasing AMPK].

Zhao XY ，Zhang LL ，Suolang QZ ，Yang GY ，Li L ，Li SB ，Chen WW ... -  《-》

Liraglutide increases FGF-21 activity and insulin sensitivity in high fat diet and adiponectin knockdown induced insulin resistance.

Yang M ，Zhang L ，Wang C ，Liu H ，Boden G ，Yang G ，Li L ... -  《-》

The Glucagon-Like Peptide-1 Analogue Liraglutide Inhibits Oxidative Stress and Inflammatory Response in the Liver of Rats with Diet-Induced Non-alcoholic Fatty Liver Disease.

Gao H ，Zeng Z ，Zhang H ，Zhou X ，Guan L ，Deng W ，Xu L ... -  《-》

Blockade of interleukin 6 signalling ameliorates systemic insulin resistance through upregulation of glucose uptake in skeletal muscle and improves hepatic steatosis in high-fat diet fed mice.

Mice fed high-fat diet (HFD) demonstrate obesity-related systemic insulin resistance (IR). Aim of this study is to clarify the role of interleukin (IL)-6 in IR in vivo focusing on skeletal muscle, adipose tissue and liver. Plasma markers of IR and hepatic IL-6 signalling were examined in eight-week HFD feeding C57/BL6 mice. Furthermore, IR-related molecules in skeletal muscles, adipose tissues and livers were investigated following a single injection of anti- IL-6 receptor neutralizing antibody (MR16-1) in two-week HFD feeding mice. To investigate the role of IL-6 in hepatic steatosis by prolonged HFD, hepatic triglyceride accumulation was assessed in eight-week HFD feeding mice with continuous MR16-1 treatment. High-fat diet for both 2 and 8 weeks elevated plasma IL-6, insulin and leptin, which were decreased by MR16-1 treatment. A single injection of MR16-1 ameliorated IR as assessed by glucose and insulin tolerance test, which may be attributable to upregulation of glucose transporter type 4 via phosphorylation of AMP-activated protein kinase as well as upregulation of peroxisome proliferator-activated receptor alpha in livers and, particularly, in skeletal muscles. MR16-1 also decreased mRNA expression of leptin and tumour necrosis factor-alpha and increased that of adiponectin in adipose tissue. High-fat diet for 8 weeks, not 2 weeks, induced hepatic steatosis and increased hepatic triglyceride content, all of which were ameliorated by MR16-1 treatment. Blockade of excessive IL-6 stimulus ameliorated HFD-induced IR in a skeletal muscle and modulated the production of adipokines from an early stage of NAFLD, leading to prevention of liver steatosis for a long term.

Yamaguchi K ，Nishimura T ，Ishiba H ，Seko Y ，Okajima A ，Fujii H ，Tochiki N ，Umemura A ，Moriguchi M ，Sumida Y ，Mitsuyoshi H ，Yasui K ，Minami M ，Okanoue T ，Itoh Y ... -  《-》