Stromal Cell Derived Factor-1 Promotes Hepatic Insulin Resistance via Inhibiting Hepatocyte Lipophagy

Saturated fatty acid (SFA) accumulation in liver decreases hepatocyte lipophagy, a type of selective Autophagy that degrades intracellular lipid droplets, leading to hepatic Insulin resistance (IR), which contributes to simultaneous increases in liver glucose production and fat synthesis, resulting in hyperglycemia and dyslipidemia traits of type 2 diabetes mellitus (T2DM). Stromal cell derived factor-1 (SDF-1), a cytokine produced by hepatocytes, inhibits Autophagy. In this study, we evaluated the hypothesis that SDF-1 promoted hepatic IR via inhibiting hepatocyte lipophagy during T2DM. Furthermore, we probed the downstream pathway participating in the role of SDF-1. The results showed that the neutralising of SDF-1 improved hepatic IR via promoting hepatocyte lipophagy in a mouse high-fat and high sucrose diet (HFHSD)-induced T2DM model. In vitro, SDF-1 expression and release increased in palmitic acid (PA, a kind of SFA)-treated hepatocytes. Meanwhile, SDF-1 bound to up-regulated C-X-C Chemokine Receptor type 4 (CXCR4) and C-X-C Chemokine Receptor type 7 (CXCR7) on PA-treated hepatocytes. Subsequently, SDF-1 inhibited lipophagy in PA-treated hepatocytes via CXCR4, rather than CXCR7. Finally, SDF-1/CXCR4/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway-inhibited lipophagy promotes PA-induced hepatocyte IR. Collectively, this study discovered that SDF-1 might inhibit lipophagy in SFA-treated hepatocytes to promote hepatic IR via CXCR4/Akt/mTOR pathway.

hepatic insulin resistance; hepatocyte; lipophagy; stromal cell derived factor‐1.