Loss of Hepatocyte FOXA3 Improves MASH and Atherosclerosis in Hyperlipidemic Ldlr-Deficient Mice

Forkhead box protein A3 (FOXA3), also known as hepatocyte nuclear factor 3g (HNF3g), is a member of the FOX family of transcription factors and regulates lipid and glucose metabolism and liver regeneration. Hepatic FOXA3 is reduced in obesity and patients with metabolic dysfunction-associated steatohepatitis (MASH). So far, it remains unknown whether hepatic FOXA3 is essential for regulating lipid metabolism or metabolic dysfunction-associated liver disease (MASLD). In this study, we first investigated whether genetic inactivation of hepatocyte <i>Foxa3</i> affected the development of MASLD/MASH in C57BL/6 mice and then explored whether loss of hepatocyte <i>Foxa3</i> regulated atherosclerosis development in <i>Ldlr</i>-deficient mice. Inactivation of <i>Foxa3</i> in hepatocytes did not affect the development of Western diet-induced MASLD/MASH in C57BL/6 mice but attenuated MASH development in Western diet-fed <i>Ldlr</i>-deficient mice. Moreover, genetic loss of hepatocyte <i>Foxa3</i> ameliorated hyperlipidemia and atherosclerosis in <i>Ldlr</i>-deficient mice. In <i>Ldlr</i>-deficient mice, loss of hepatocyte <i>Foxa3</i> resulted in reduced expression of lipogenic, pro-inflammatory, or fibrogenic genes in the liver and reduced cholic acid levels in plasma and bile. Thus, hepatocyte FOXA3 loss confers protection against the development of MASH and atherosclerosis in hyperlipidemic <i>Ldlr</i>-deficient mice.