Hepatic triglyceride synthesis pathway (HTS pathway)

The hepatic triglyceride synthesis pathway is a multi-step metabolic process in the liver that converts fatty acids and glycerol-3-phosphate into triglycerides for storage or export as very-low-density lipoproteins (VLDL) (Sanders & Griffin, Metabolism, 2016). This pathway incorporates fatty acids from three sources: dietary intake, adipose tissue lipolysis, and de novo lipogenesis (DNL), the latter of which is often pathologically elevated in metabolic disorders (Smith et al., JCI, 2020). Key regulatory enzymes in this process include Acetyl-CoA carboxylase (ACC), Fatty acid synthase (FASN), and Diacylglycerol O-acyltransferase (DGAT), which serve as primary therapeutic targets (Loomba et al., Hepatology, 2021). Chronic overactivation of this pathway leads to hepatic steatosis, a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) (Rinella et al., Journal of Hepatology, 2023). Pharmacological inhibitors of ACC (e.g., firsocostat), FASN (e.g., denifanstat), and DGAT2 (e.g., ervogastat) are currently under investigation to reduce hepatic fat content and mitigate liver injury (ClinicalTrials.gov, 2024). However, therapeutic challenges include managing potential side effects like paradoxical increases in serum triglycerides or dermatological toxicities associated with systemic inhibition of lipid synthesis (Kim et al., Nature Communications, 2017).

Other names

De novo lipogenesisGlycerol-3-phosphate pathwayHepatic lipogenesisDNL pathway

Inhibition of rate-limiting enzymes such as Acetyl-CoA carboxylase (ACC), Fatty acid synthase (FASN), and Diacylglycerol O-acyltransferase 2 (DGAT2) to decrease the assembly and secretion of triglycerides (Loomba et al., Hepatology, 2021).