Mechanism of Metabolic Dysfunction-associated Steatotic Liver Disease: Important role of lipid metabolism

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, has a high global prevalence and can progress to metabolic dysfunction-associated steatohepatitis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of MASLD is primarily driven by disturbances in hepatic lipid metabolism, involving six key processes: increased hepatic fatty acid uptake, enhanced fatty acid synthesis, reduced oxidative degradation of fatty acids, increased cholesterol uptake, elevated cholesterol synthesis, and increased bile acid synthesis. Consequently, maintaining hepatic lipid metabolic homeostasis is essential for effective MASLD management. Numerous novel molecules and Chinese proprietary medicines have demonstrated promising therapeutic potential in treating MASLD, primarily by inhibiting lipid synthesis and promoting lipid oxidation. In this review, we summarized recent research on MASLD, elucidated the molecular mechanisms by which lipid metabolism disorders contribute to MASLD pathogenesis, and discussed various lipid metabolism-targeted therapeutic approaches for MASLD.

Keywords: Chinese proprietary medicine; Cholesterol metabolism; Lipid metabolism; Lipogenesis; Lipolysis; MASLD; lipid metabolism-targeted drugs.

Fig. 1. Fatty acid metabolism. Fatty acid uptake by the liver depends on fatty acid transport carriers, including FATP, CD36, and CAV-1.

The raw material for de novo fatty acid synthesis is acetyl-CoA, which can be obtained via the citrate shuttle pathway or from acetic acid. ACC and FASN catalyze the conversion of acetyl-CoA into saturated palmitic acid, which can be further modified into other fatty acids by enzymes such as SCD. De novo fatty acid synthesis is promoted by SREBPs. Conversely, the β-oxidation of fatty acids occurs in the mitochondria. Fatty acids are converted into fatty acyl-CoA by ACSL and transported via CPT-1 before being oxidized to acetyl-CoA. Fatty acid β-oxidation is promoted by PPARα. FAs, fatty acids; FASN, fatty acid synthase; SREBP, sterol-regulatory element binding protein; FASN, fatty acid synthase; ACC, acetyl-CoA carboxylase; ACLY, ATP citrate lyase; ACSS, acetyl-CoA synthetase; ACSL, acyl-CoA synthetase; PPAR, peroxisome proliferator-activated receptor; CPT-1, carnitine palmitoyltransferase-1.

Fig. 2. Cholesterol metabolism.

The process of cholesterol synthesis is complex and can be roughly divided into three stages: synthesis of IPP from acetyl-CoA, synthesis of squalene, and conversion of squalene to cholesterol. HMGCR and SM are the key enzymes in cholesterol synthesis. The primary route of cholesterol production is bile acid synthesis catalyzed by CTP7A1. FXR is an important regulator of cholesterol metabolism; Its activation inhibits CTP7A1, leading to the inhibition of bile acid synthesis. FXR, farnesoid X receptor; CYP7A1, cholesterol 7α-hydroxylase; SM, squalene monooxygenase; HMGCR, 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase; IPP, isopentenyl pyrophosphate; SREBP, sterol-regulatory element binding protein; PPAR, peroxisome proliferator-activated receptor; FAs, fatty acids; ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; ACLY, ATP citrate lyase.