Integrin-linked kinase promotes hepatic fat accumulation via F-actin stabilization-dependent CD36 plasma membrane localization.

Increased hepatic lipid accumulation occurs in high-fat diet (HFD)-induced insulin resistance. Integrin-linked kinase (ILK) contributes to HFD-induced hepatic insulin resistance by increasing hepatic triglyceride content. How ILK promotes HFD-induced hepatic fatty acid accumulation is underexplored. ILK favors the formation of F-actin bundling and is upregulated following HFD. Moreover, the fatty acid transporter CD36 localizes to membrane ruffles rich in F-actin following HFD. Thus, we investigated whether ILK-mediated F-actin stabilization and liver fatty acid uptake are mechanistically linked. HFD-fed mice lacking ILK in hepatocytes have reduced hepatic F-actin abundance, CD36 plasma membrane localization, and intracellular lipid accumulation. ILK-null cells treated with the F-actin stabilizer jasplakinolide increased cortical F-actin polymerization, plasma membrane-associated CD36, and intracellular lipid uptake. CD36 inhibition reduced lipid uptake in jasplakinolide-treated ILK-null cells, confirming that F-actin-induced CD36 plasma membrane localization promotes lipid accumulation. Thus, ILK regulates intracellular lipid transport by linking CD36 to an F-actin-rich cytoskeleton.