Hepatic fatty acid and cholesterol synthesis pathway

The hepatic fatty acid and cholesterol synthesis pathway is a fundamental metabolic process in the liver responsible for the de novo production of lipids and sterols (NIH, 2023). This pathway involves several key enzymes, most notably HMG-CoA reductase (HMGCR) for cholesterol synthesis and Acetyl-CoA carboxylase (ACC) for fatty acid synthesis (StatPearls, 2023). Dysregulation of these processes leads to the accumulation of intrahepatic fat and elevated circulating lipids, contributing to diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and cardiovascular disease (Journal of Lipid Research, 2020). Pharmacological strategies targeting this pathway typically involve the inhibition of these rate-limiting enzymes to reduce lipid burden. For instance, statins are widely used to inhibit HMGCR and lower LDL cholesterol, while ACC inhibitors like firsocostat are being investigated to reduce hepatic steatosis (Hepatology, 2021). Additionally, ATP citrate lyase (ACLY) inhibitors like bempedoic acid act upstream in the pathway to lower cholesterol levels (PubMed, 2022).

Other names

De novo lipogenesis (DNL)Mevalonate pathwayHepatic lipid synthesisHepatic lipogenesis

The pathway is targeted through the pharmacological inhibition of its rate-limiting enzymes. HMG-CoA reductase inhibitors (statins) prevent the synthesis of mevalonate, a critical precursor to cholesterol (StatPearls, 2023). Acetyl-CoA carboxylase (ACC) inhibitors block the production of malonyl-CoA, thereby inhibiting fatty acid synthesis and promoting fatty acid oxidation (Hepatology, 2021). ATP citrate lyase (ACLY) inhibitors, such as bempedoic acid, reduce the availability of acetyl-CoA for both cholesterol and fatty acid synthesis (PubMed, 2022).