Acetyl-CoA carboxylase (ACC1/ACC2) + Diacylglycerol acyltransferase 2

Class

Combination of two small-molecule inhibitors: clesacostat (ACC inhibitor, PF-05221304) + ervogastat (DGAT2 inhibitor, PF-06865571)

Pathway

De novo lipogenesis (ACC) combined with triglyceride esterification (DGAT2) — dual blockade intended to reduce both fatty-acid synthesis and downstream diacylglycerol/triglyceride buildup while limiting ACC-inhibitor-associated hypertriglyceridemia

Notes

original target text: Acetyl-CoA carboxylase (ACC1/ACC2) + Diacylglycerol acyltransferase 2 (DGAT2)

Acetyl-CoA carboxylase (ACC) and diacylglycerol acyltransferase 2 (DGAT2) are two enzymes that act at different points in the liver's fat-building machinery. ACC catalyzes the first committed step of fatty acid synthesis, converting acetyl-CoA into malonyl-CoA; DGAT2 catalyzes the last step of triglyceride formation, joining a fatty acid to a diacylglycerol molecule. In fatty liver disease, the liver both manufactures excess fat internally (de novo lipogenesis) and stores it as triglyceride, driving the steatosis and lipid-related cell stress that underlie conditions such as non-alcoholic fatty liver disease and its more severe form, steatohepatitis. Blocking ACC alone reduces new fat synthesis but has a known side effect: it tends to raise circulating triglyceride levels, because fatty acid flux is redirected toward esterification pathways. Pairing an ACC inhibitor with a DGAT2 inhibitor addresses this by blocking the very enzyme responsible for that downstream esterification, limiting triglyceride accumulation while still curbing lipogenesis upstream. This dual-enzyme, dual-drug strategy illustrates a broader pharmacological principle: combining agents with complementary and counterbalancing mechanisms can achieve an effect neither could sustain safely alone, reducing liver fat without the metabolic trade-off of either enzyme's inhibition in isolation.