Liraglutide Alleviates Hepatic Steatosis and Liver Injury in T2MD Rats via a GLP-1R Dependent AMPK Pathway

Abstract

Non-alcoholic fatty liver disease (NAFLD), ranging from non-alcoholic fatty liver to non-alcoholic steatohepatitis, can be prevalent in patients with type 2 diabetes mellitus (T2DM). However, no antidiabetic drug has been approved for the treatment of NAFLD in T2DM patients. Multiple daily injections of basal-bolus insulin are often the final therapeutic option for T2DM. We found that insulin treatment aggravated hepatic steatosis and oxidative stress in Zucker diabetic fatty (ZDF) rats. In addition to glycaemic control, we demonstrated the stimulatory role of liraglutide in relieving hepatic steatosis and liver injury in ZDF rats. Interestingly, liraglutide could also alleviate insulin-aggravated hepatic fatty accumulation. The glucagon-like peptide-1 (GLP-1) agonists liraglutide and Ex-4 activated the expression of peroxisome proliferator-activated receptor alpha (PPARα) via a GLP-1 receptor-dependent 5′ AMP-activated protein kinase pathway. As a nuclear transcription factor, PPARα could mediate the effect of GLP-1 in alleviating hepatic steatosis by differentially regulating the expression of its target genes, including acetyl CoA carboxylase and carnitine palmitoyl transferase la both in vitro and in vivo. Moreover, GLP-1 could relieve liver injury by decreasing oxidative stress stimulated by hepatic steatosis. Insulin might aggravate hepatic steatosis and liver injury by inhibiting GLP-1R expression. The findings indicate the feasibility of liraglutide treatment combined with basal insulin in attenuating hepatic steatosis and liver injury in ZDF rats. This knowledge, and the evidence for the underlying mechanism, provide a theoretical basis for the combination treatment recommended by the latest clinical practice guidelines for T2DM.

Protective Effects and Mechanisms of Polyethylene Glycol Loxenatide Against Hyperglycemia and Liver Injury in db/db diabetic Mice

“…In the liver, GLP-1 stimulated the phosphorylation of AMPK and expression of Sirt1, then activated AMPK can phosphorylate ACC and reduce the production of malonyl-coA, thus up-regulating CPT1 expression, reducing FAT level, promoting fatty acid oxidation and reducing lipid deposition (Mottillo et al, 2016;Liu et al, 2015;Wan et al, 2021;O'Neill et al, 2013;Ben-Shlomo et al, 2011). Lira, as demonstrated in recent years, improves insulin resistance and hepatic lipid deposition in T2DM rats fed with a high-fat diet and promotes lipid degradation in liver and adipose tissues through activation of the AMPK pathway (He et al, 2016;He et al, 2020;Zhou et al, 2020). Similarly, our study demonstrated that PEG-Loxe, Lira, and Loxe notably upregulated the levels of Sirt1, p-AMPK, and p-ACC in the liver.…”

“…Paraffin-embedded pancreatic tissues (4 μm thick) were dewaxed, hydrated, and sealed with 5% bovine serum albumin (BSA) solution for 30 min at room temperature. The samples were then incubated with anti-insulin or anti-GLP-1R overnight and horseradish peroxidase (HRP)-conjugated anti-rabbit secondary antibody for 30 min the following day, stained with stable diaminobenzidine (DAB) solution, re-stained with hematoxylin, dehydrated, blocked, and observed and imaged using an Olympus BX51 microscope (Tokyo, Japan) ( Zhou et al, 2020 ).…”

“…Western blot was performed as described previously ( Zhou et al, 2020 ). Liver or pancreatic tissues were homogenized with RIPA lysate containing 1% PMSF protease inhibitor and phosphatase inhibitor, and total tissue protein was extracted via centrifugation for 10 min.…”

Current Options and Future Directions for NAFLD and NASH Treatment

“…Intraperitoneal treatment of a synthetic peptide AWRK6, a candidate agonist of GLP-1 , can improve hepatic steatosis, glucose metabolism, and obesity in high energy diet (HED)-induced MAFLD mice, via modulating phosphoinositide 3-kinase ( PI3K )/Protein kinase B ( AKT )/AMP-activated protein kinase (AMPK) /acetyl-CoA carboxylase (ACC) signaling pathway [ 52 ]. In diabetic fatty rats, GLP-1 agonists liraglutide and Ex-4 can enhance the expression of PPARα through a GLP-1 receptor/ AMPK signaling pathway [ 53 ]. However, a cohort study showed that the treatment of GLP-1 agonist did not decrease the risk of NAFLD development compared to insulin treatment [ 54 ].…”

Preventing Oxidative Stress in the Liver: An Opportunity for GLP-1 and/or PASK

“…GLP-1/exendin-4 treatments have been associated with reduced oxidative stress. For example, antioxidant enzymes (SOD, glutathione reductase, CAT, and GPx), as well as glutathione levels, are improved, while other stress markers (lipid peroxidation and nonenzymatic glycosylated proteins) are reduced [ 95 , 131 ].…”