Mechanisms of increased triglyceride synthesis and lipolysis induced by Fatty acid Transport Protein 4 deficiency in hepatocytes

Background Increased expression of adipose Fatty Acid Transport Protein 4 (FATP4) is observed in obese individuals. FATP4 mutations are associated with blood triglycerides (TG) and insulin resistance. FATP4 deficiency may cause metabolic risks. We have reported an increase in secreted TG, glycerol, and non-esterified free fatty acids (NEFA) in liver-specific Fatp4-deficient (L-FATP4-/-) mice fed with high-sugar and high-fat diets. These lipids were also elevated in FATP4-deficient HepG2 (HepKO) cells. Here, we investigated the mechanisms for these increases.

Methods Two models of FATP4 deficiency were used including HepKO cells generated by CRISPR/Cas9 technology and hepatocytes isolated from L-FATP4-/- mice. These cells were treated with 600 microM oleate or control BSA for 4 h and subjected to lipid and expression analyses.

Results Both HepKO and L-FATP4-/- hepatocytes showed an increase in TG, glycerol, and NEFA in cells and supernatants. This TG increase led to an increase in VLDL and HDL secretion as well as cellular MTTP and ApoB mRNA expression. TG and lipoprotein levels were further increased upon oleate treatment. Expression of CD36, FATP5, FATP2, and fatty acid synthase (FAS) was also increased in HepKO and L-FATP4-/- hepatocytes suggesting increased fatty acid uptake and de novo synthesis. TG lipolysis in FATP4-deficient cells was likely due to the action of plasma-membrane hepatic lipase (HL) but not cytosolic ATGL and HSL.

Conclusions Hepatocyte FATP4 deficiency induced an elevation of CD36, FATP5, FATP2, FAS, and HL resulting exaggerated secreted lipids. Our study may provide mechanistic insights for metabolic abnormalities seen in individuals with FATP4 mutations.

Publikationsverlauf

Artikel online veröffentlicht:
26. Januar 2022