Tissue-specific regulation of PNPLA3 promotes lipid remodeling in response to dietary and temperature stress.

A variant in PNPLA3, an enzyme that promotes transfer of long-chain polyunsaturated fatty acids (LCPUFAs) from triglycerides to phospholipids in lipid droplets (LDs), is a major risk factor for steatotic liver disease. At thermoneutrality, PNPLA3 is easily detected in liver and increases with feeding; the protein is undetectable in adipose tissue, despite significantly higher Pnpla3 mRNA levels. Cold exposure or β3-adrenergic stimulation did not alter hepatic PNPLA3 but triggered a >19-fold increase in adipose PNPLA3, accompanied by a >75% reduction in Pnpla3 mRNA. This effect occurred in cultured adipocytes and was blocked by inhibiting Protein Kinase A or AKT. The predominant cause of the kinase-dependent increase in adipocyte PNPLA3 was reduced degradation. We speculate that the tissue-specific regulation of PNPLA3 redistributes LCPUFAs to the LD surface to enhance lipid remodeling and promote fatty acid mobilization in response to feeding in liver and to cold in adipose tissue.