Hepatic Lipid Metabolism in Fatty Liver Disease

Hepatic lipid metabolism encompasses the coordinated processes by which the liver acquires, synthesises, stores and exports fatty acids and their derivatives. In healthy individuals, the liver takes up circulating non-esterified fatty acids, synthesises new fatty acids via de novo lipogenesis, esterifies fatty acids into triglycerides and secretes them as very low-density lipoprotein (VLDL). Excess lipid influx or overactive lipogenic pathways lead to intrahepatic triglyceride accumulation, termed steatosis. Persistent steatosis triggers lipotoxic stress, inflammation and activation of hepatic stellate cells, progressing to non-alcoholic steatohepatitis (NASH) and fibrosis. Key enzymes such as acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN) and diacylglycerol acyltransferases (DGATs) regulate lipid synthesis, while β-oxidation in mitochondria and peroxisomes mediates lipid clearance. Dysregulation of these pathways underpins the spectrum of fatty liver disease, with systemic consequences for insulin resistance, cardiovascular risk and overall metabolic health. Emerging research seeks to balance lipid flux by inhibiting lipogenesis, enhancing fatty acid oxidation or modulating lipid export, with the goal of reversing steatosis, alleviating inflammation and preventing fibrotic remodelling.

Research from Nature Portfolio

Recent studies have shown that blocking FASN alters the fate of dietary polyunsaturated fatty acids (PUFAs) in the liver. Inhibition of FASN increases PUFA uptake via the lysophosphatidylcholine transporter MFSD2A and promotes their incorporation into triglycerides through diacylglycerol O-acyltransferase 2, thereby reducing hepatic triacylglycerol content in high-fat–fed models. This work suggests that combining PUFA supplementation with FASN inhibition may represent a novel strategy to correct lipid imbalances in fatty liver disease. In addition, structural characterisation of the central non-catalytic domain of acetyl-CoA carboxylase has revealed regulatory phosphorylation sites that control large-scale conformational changes required for malonyl-CoA production. These insights into ACC architecture and regulation offer potential routes to develop highly selective ACC modulators that can attenuate de novo lipogenesis without off-target effects.

Hepatic Lipid Metabolism in Fatty Liver Disease publication trend

The graph below shows the total number of articles in hepatic lipid metabolism in fatty liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

De novo lipogenesis (DNL): Metabolic pathway converting acetyl-CoA into fatty acids, primarily regulated by ACC and FASN.

Fatty acid synthase (FASN): Multienzyme complex that catalyses the terminal steps of DNL, producing palmitate from malonyl-CoA.

Acetyl-CoA carboxylase (ACC): Enzyme converting acetyl-CoA to malonyl-CoA, committing substrate to fatty acid biosynthesis.

Diacylglycerol acyltransferase 2 (DGAT2): Enzyme catalysing the final acylation step to synthesise triglycerides from diacylglycerol.

Very low-density lipoprotein (VLDL): Lipoprotein particle secreted by the liver to deliver triglycerides and cholesterol to peripheral tissues.

References

1. Denifanstat for the treatment of metabolic dysfunction-associated steatohepatitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2b trial. The Lancet Gastroenterology & Hepatology (2024).
2. Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use. Nature Communications (2024).
3. TRIM56 protects against non-alcoholic fatty liver disease via promoting the degradation of fatty acid synthase. Journal of Clinical Investigation (2024).
4. Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on nonalcoholic steatohepatitis and hepatic fibrosis in mice. Cell Reports Medicine (2023).
5. The dynamic organization of fungal acetyl-CoA carboxylase. Nature Communications (2016).