Halting Hypercaloric Feeding in Liver Chimeric Mice Rapidly Resolves Human Hepatocyte Steatosis

Hepatocyte steatosis in metabolic dysfunction-associated steatotic liver disease can change quickly based on the types and amounts of calories consumed. This study investigates how dietary changes affect steatosis resolution in human hepatocytes and whether patatin-like phospholipase domain-containing 3 (PNPLA3) genetic variants influence this process.

Chimeric mice engrafted with PNPLA3 148-isoleucine variant (huFNRG^148I) or PNPLA3 148-methionine variant (PNPLA3-148M, huFNRG^148M) hepatocytes were fed a Western diet (WD) and/or 10% sucrose water (10%S) to induce steatosis. After 4 weeks, mice either resumed chow to promote steatosis resolution or continued on WD or 10%S.

After discontinuing WD and 10%S, steatosis in huFNRG^148I mice improved 50% within 1 week, with full resolution occurring by 4 weeks. Reducing huFNRG^148I calorie intake by switching to either WD or 10%S resulted in milder improvements. In contrast, huFNRG^148M mice showed minimal changes in steatosis 1 week after stopping WD and 10%S with persistent steatohepatitis activity. Surprisingly, after 4 weeks of WD and 10%S many pro-inflammatory proteins were lower in huFNRG^148M than huFNRG^148I serum yet more inflammation markers rose after stopping the diet. In addition, steatotic huFNRG^148M livers were enriched in many phospholipids and long-chain triglycerides and evolved differently from huFNRG^148I livers, including the retention of many polyunsaturated phosphatidylethanolamines and long-chain diglycerides.

PNPLA3 3 148-isoleucine variant human hepatocytes in chimeric mice rapidly resolve steatosis with a gradual improvement in steatohepatitis activity, which is delayed in PNPLA3-148M hepatocytes. This supports a model in which altered lipid mobilization in PNPLA3-148M hepatocytes contributes to more active steatohepatitis.