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

Area of Science:

• Metabolism
• Cell Biology
• Endocrinology

Background:

• Saturated fatty acid accumulation in the liver impairs hepatocyte lipophagy, leading to hepatic insulin resistance (IR).
• Stromal cell derived factor-1 (SDF-1), a cytokine produced by hepatocytes, is known to inhibit autophagy.
• Hepatic IR contributes to hyperglycemia and dyslipidemia, hallmarks of type 2 diabetes mellitus (T2DM).

Purpose of the Study:

• To investigate if SDF-1 promotes hepatic IR by inhibiting hepatocyte lipophagy in T2DM.
• To elucidate the downstream signaling pathway involved in SDF-1's role in hepatic IR.

Main Methods:

• Utilized a mouse model of T2DM induced by a high-fat and high-sucrose diet (HFHSD).
• Examined SDF-1 expression and its interaction with receptors (CXCR4, CXCR7) in palmitic acid (PA)-treated hepatocytes in vitro.
• Investigated the SDF-1/CXCR4/AKT/mTOR signaling pathway's effect on lipophagy and IR.

Main Results:

• Neutralizing SDF-1 ameliorated hepatic IR by promoting hepatocyte lipophagy in the HFHSD-induced T2DM mouse model.
• SDF-1 expression and release increased in PA-treated hepatocytes, binding to CXCR4 and CXCR7.
• SDF-1 inhibited lipophagy in PA-treated hepatocytes specifically via CXCR4, not CXCR7.
• The SDF-1/CXCR4/AKT/mTOR pathway was identified as a key mediator inhibiting lipophagy and promoting PA-induced hepatic IR.

Conclusions:

• SDF-1 plays a crucial role in promoting hepatic IR in T2DM.
• SDF-1 inhibits hepatocyte lipophagy through the CXCR4/AKT/mTOR pathway in response to saturated fatty acids.
• Targeting the SDF-1/CXCR4 axis presents a potential therapeutic strategy for managing hepatic IR in T2DM.