Liraglutide modulates gut microbiome and attenuates nonalcoholic fatty liver in db/db mice.

Liraglutide, a glucagon-like peptide-1(GLP-1) analog, is effective for the treatment of type II diabetes and nonalcoholic fatty liver disease (NAFLD). It was proved that gut microbiome plays a role in the development of NAFLD. This study aims to observe the therapeutic effect of liraglutide on nonalcoholic fatty liver (NAFL) in mice and effect on the gut microbial community. The db/db mice were used as the NAFL model, and lactulose was used as the positive control drug. Hepatic triglyceride, liver histopathology, and indices of glucolipid metabolism, including fasting blood glucose, fasting insulin, insulin resistance index and blood lipids were evaluated after treatment of liraglutide or lactulose for four weeks. The colonic microbiome of the mice was analyzed by 16S rRNA gene sequencing. Liraglutide significantly reduced the hepatic triglyceride (TG) content, alanine aminotransferase (ALT) activity, fasting blood glucose, insulin resistance and serum low density lipoprotein (LDL) in the db/db mice. In terms of hepatic pathologies, hepatic steatosis was significantly improved after liraglutide treating. Microbiome analysis revealed that liraglutide significantly increased the abundance of Akkermansia, Romboutsia, norank_f_Bacteroidales_S24-7_group, and decreased the abundance of Klebsiella, Anaerotruncus, Bacteroides, Lachnospiraceae_UCG-001, Lachnospiraceae_NK4A136_group, Ruminiclostridium, uncultured_f__Ruminococcaceae, and Desulfovibrio. The results of the present study suggested that liraglutide had a certain therapeutic effect on fatty liver in db/db mice and had an impact on the composition of the intestinal microflora, especially some bacteria related to glucolipid metabolism and intestinal inflammation. Affecting gut microbiome might be a potential mechanism of liraglutide in treating NAFL.

Liu Q ，Cai BY ，Zhu LX ，Xin X ，Wang X ，An ZM ，Li S ，Hu YY ，Feng Q ... -  《-》

The HIF-2α/PPARα pathway is essential for liraglutide-alleviated, lipid-induced hepatic steatosis.

Liraglutide has been demonstrated to alleviate hepatic steatosis in clinical practice, but the underlying mechanism remains unclear. Our previous study indicated that the HIF-2α/PPARα pathway was involved in hepatic lipid accumulation induced by hypoxia.We aimed to investigate whether liraglutide could alleviate lipid-induced hepatic steatosis via the HIF-2α/PPARα pathway. Whole-body HIF-2α heterozygous knockout (HIF-2α+/-) mice and littermate wild-type (WT) mice were successfully established. Male mice challenged with a high-fat diet were treated with liraglutide (0.6 mg/kg/d) or normal saline by intraperitoneal injection for 4 weeks. We observed that, compared with WT mice, many indicators of HIF-2α+/- mice improved, including GTT, ITT, fasting blood glucose, body weight, liver weight, and lipid profile in serum or liver lipid deposition, and the expression level of PPARα, mitochondrial function genes, and fatty acid oxidation genes were upregulated, while those of HIF-2α and lipogenesis genes were downregulated significantly. After liraglutide treatment in WT mice, we found that significant improvements were observed in the fat mass, GTT, ITT, fasting blood glucose, body weight, liver weight, lipid profile in serum or liver lipid deposition; the β-oxidation genes were upregulated and the lipogenesis genes were downregulated; and the abundance of intestinal Akkermansia muciniphila increased significantly. However, the effects of liraglutide on WT mice were not observed in HIF-2α+/- mice. In addition, in the HepG2 steatotic hepatocyte model, liraglutide alleviated lipid deposits by repressing lipid synthesis and enhancing fatty acid β-oxidation, which were substantially suppressed by the HIF-2α modulators. Therefore, the HIF-2α/PPARα pathway is essential for liraglutide-alleviated lipid-induced hepatic steatosis.

Wang H ，Wang L ，Li Y ，Luo S ，Ye J ，Lu Z ，Li X ，Lu H ... -  《-》

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 ... -  《-》

Novel insulin sensitizer MSDC-0602K improves insulinemia and fatty liver disease in mice, alone and in combination with liraglutide.

Insulin sensitizers and incretin mimetics are antidiabetic agents with vastly different mechanisms of action. Thiazolidinedione (TZD) insulin sensitizers are associated with weight gain, whereas glucagon-like peptide-1 receptor agonists can induce weight loss. We hypothesized that combination of a TZD insulin sensitizer and the glucagon-like peptide-1 receptor agonist liraglutide would more significantly improve mouse models of diabetes and nonalcoholic steatohepatitis (NASH). Diabetic db/db and MS-NASH mice were treated with the TZD MSDC-0602K by oral gavage, liraglutide (Lira) by s.c. injection, or combination 0602K+Lira. Lira slightly reduced body weight and modestly improved glycemia in db/db mice. Comparatively, 0602K-treated and 0602K+Lira-treated mice exhibited slight weight gain but completely corrected glycemia and improved glucose tolerance. 0602K reduced plasma insulin, whereas Lira further increased the hyperinsulinemia of db/db mice. Surprisingly, 0602K+Lira treatment reduced plasma insulin and C-peptide to the same extent as mice treated with 0602K alone. 0602K did not reduce glucose-stimulated insulin secretion in vivo, or in isolated islets, indicating the reduced insulinemia was likely compensatory to improved insulin sensitivity. In MS-NASH mice, both 0602K or Lira alone improved plasma alanine aminotransferase and aspartate aminotransferase, as well as liver histology, but more significant improvements were observed with 0602K+Lira treatment. 0602K or 0602K+Lira also increased pancreatic insulin content in both db/db and MS-NASH mice. In conclusion, MSDC-0602K corrected glycemia and reduced insulinemia when given alone, or in combination with Lira. However, 0602K+Lira combination more significantly improved glucose tolerance and liver histology, suggesting that this combination treatment may be an effective therapeutic strategy for diabetes and NASH.

Kamm DR ，Pyles KD ，Sharpe MC ，Healy LN ，Colca JR ，McCommis KS ... -  《-》

[Correlation analysis of gut microbiota and biochemical indexes in patients with non-alcoholic fatty liver disease].

Ren SM ，Mei L ，Huang H ，Cao SF ，Zhao RH ，Zheng PY ... -  《-》