Adipose-specific MTP deficiency protects against hepatic steatosis up upregulating PPARα activity

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health concern. Better understanding of factors that prevent hepatic lipid accumulation may help design new strategies to prevent or treat MASLD. We have previously shown that adipocyte microsomal triglyceride transfer protein (MTP) regulates intracellular lipolysis by inhibiting adipose triglyceride lipase (ATGL) activity. Here, we show that adipose-specific MTP knockout mice (A-Mttp−/−) fed an obesogenic diet exhibit moderately high plasma triglyceride levels and less hepatic steatosis compared to their wild-type counterparts. Mechanistic studies revealed that high plasma triglycerides are due to increased hepatic triglyceride synthesis and production of triglyceride-rich lipoproteins from the livers of A-Mttp−/− mice. In addition, hepatocytes from these mice showed increased fatty acid oxidation and this could be a contributing factor for less hepatic steatosis. Studies aimed at understanding how adipose MTP regulated hepatic triglyceride-rich lipoprotein production and fatty acid oxidation revealed that adipose MTP modulates the release of agonists that activate hepatic PPARα activity. Our study highlights the significance of the regulated movement of fatty acid from adipose tissue to the liver in maintaining a healthy liver. It is likely that adipocyte fatty acid release can be modulated to reduce hepatic steatosis.