PR002572 (Project)

Description:The PNPLA3(I148M) mutation is associated with increased risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD). To better understand how PNPLA3(I148M) mutation impacts hepatic lipid metabolism, we conducted lipidomics analysis from Hep3B cells expressing wild type or I148M mutant PNPLA3 and cultured in media plus or minus oleic acid. Our studies revealed widespread changes in the lipidomic profiles of Hep3B cells expressing PNPLA3(I148M) compared to Hep3B cells expressing wild type PNPLA3, particularly after exposure to exogenous oleic acid in the culture media. Of particular note, we report decreases in the relative abundance of phosphatidylcholines and other phospholipids containing polyunsaturated fatty acids (PUFA) like arachidonic acid. These changes in phospholipid PUFA content lead to changes in membrane fluidity that impact the ability of cells carrying the PNPLA3(I148M) to secrete apolipoprotein B (apoB)-rich very low density lipoproteins. This impaired lipid secretory phenotype leads to an accumulation of triglycerides, which was verified by our lipidomics observation that Hep3B cells expressing PNPLA3(I148M) contain increases in the relative abundance of many triglycerides relative to PNPLA3 wild type Hep3B cells.