lipogenesis

Lipogenesis begins with citrate shuttled from mitochondria to cytosol, which is cleaved by ATP-citrate lyase into acetyl-CoA and oxaloacetate. Acetyl-CoA carboxylase (ACC), the rate-limiting enzyme, converts acetyl-CoA to malonyl-CoA using biotin as a cofactor; ACC is activated by insulin/citrate and inhibited by glucagon/epinephrine (via AMPK-mediated phosphorylation) and by malonyl-CoA's own downstream product palmitate (feedback inhibition). Fatty acid synthase (FAS) then elongates malonyl-CoA and acetyl-CoA units into palmitate using NADPH (generated by the HMP shunt and malic enzyme). Newly synthesized fatty acids are esterified with glycerol-3-phosphate to form triglycerides, packaged into VLDL by the liver, or stored in adipocytes. Insulin promotes lipogenesis by activating ACC, upregulating glucose uptake (GLUT4), and inducing lipogenic gene transcription via SREBP-1c; it also inhibits lipolysis. This pathway is clinically relevant in obesity, metabolic syndrome, and type 2 diabetes, where chronic hyperinsulinemia drives excess lipogenesis leading to hepatic steatosis (fatty liver) and dyslipidemia. Malonyl-CoA also inhibits carnitine acyltransferase I (CAT I), thereby coupling lipogenesis with inhibition of fatty acid oxidation, ensuring that the body doesn't simultaneously synthesize and break down fats. Pharmacologically, ACC is a target for anti-obesity and antifungal (biotin-related) drug development, and understanding lipogenesis is key to explaining hypertriglyceridemia in conditions like uncontrolled diabetes and alcohol use disorder (via increased NADH/acetyl-CoA from ethanol metabolism).