Dyslipidaemia and hepatic steatosis: mechanisms and implications for lipid-lowering therapy

Dyslipidaemia and hepatic steatosis are interconnected metabolic disorders, often associated with obesity and diabetes mellitus, that contribute to the burden of cardiovascular disease. Hepatic steatosis is now recognized as a specific subset of metabolic dysfunction-associated steatotic liver disease (MASLD). Several processes contribute to lipid deposition in the liver, including increased de novo lipogenesis, impaired fatty acid oxidation and reduced lipoprotein biosynthesis. Hepatic lipid accumulation can also result from lipid-lowering therapies that impair lipoprotein production, thus requiring careful monitoring of hepatic lipid content in patients taking these medications. By contrast, drugs that lower plasma levels of lipids by increasing hepatic expression of the LDL receptor do not lead to lipid accumulation in the liver; however, some patients are less responsive than others to these therapies. Therefore, new therapeutics that decrease lipoprotein production without causing steatosis are needed. Indeed, balanced modulation of hepatic lipoprotein production and secretion, as well as systemic and cellular lipid catabolism, is crucial for hepatic lipid homeostasis. Strategies that target both plasma and hepatic lipid levels will help to reduce the burden of atherosclerosis and MASLD. In this Review, we discuss mechanistic links between dyslipidaemia and hepatic steatosis, emphasizing lipid-lowering therapies and their effects on hepatic lipid accumulation.