Hepatocyte growth factor alleviates hepatic insulin resistance and lipid accumulation in high-fat diet-fed mice

Aims/introduction: Type 2 diabetes mellitus is frequently accompanied by fatty liver disease. Lipid accumulation within the liver is considered as one of the risk factors for insulin resistance. Hepatocyte growth factor (HGF) is used to treat liver dysfunction; however, the effect and mechanism of HGF on hepatic lipid metabolism are still not fully understood.

Materials and methods: Male C57BL/6 mice were induced with a high-fat diet for 12 weeks, followed by a 4-week treatment of HGF or vehicle saline. The levels of fasting blood glucose, fasting insulin and homeostatic model assessment of insulin resistance were calculated for insulin sensitivity. Biochemical plasma parameters were also measured to assess the effect of HGF on lipid accumulation. Additionally, genes in the lipid metabolism pathway were evaluated in palmitic acid-treated HepG2 cells and high-fat diet mice.

Results: HGF treatment significantly decreased the levels of fasting blood glucose, hepatic triglyceride and cholesterol contents. Additionally, HGF-regulated expression levels of sterol regulatory element-binding protein-1c/fatty acid synthase, peroxidase proliferator-activated receptor-α, and upstream nuclear receptors, such as farnesoid X receptor and small heterodimer partner. Furthermore, c-Met inhibitor could partially reverse the effects of HGF.

Conclusions: HGF treatment can ameliorate hepatic insulin resistance and steatosis through regulation of lipid metabolism. These effects might occur through farnesoid X receptor-small heterodimer partner axis-dependent transcriptional activity.