Lipogenesis

Lipogenesis is the metabolic process by which simple substrates, primarily acetyl-CoA, are converted into fatty acids, which can be stored as triglycerides or used for membrane synthesis. In humans, de novo lipogenesis occurs mainly in the liver and, to a lesser extent, in adipose tissue, and it becomes prominent after carbohydrate-rich meals.

The core pathway involves acetyl-CoA carboxylase converting acetyl-CoA to malonyl-CoA, the first committed step and rate-limiting reaction of lipogenesis. Fatty acid synthase then catalyzes a sequence of condensations and reductions that extend the carbon chain, ultimately producing palmitate (16:0). The process requires NADPH as a reducing agent and uses cytosolic acetyl-CoA generated from citrate that is transported out of mitochondria. Downstream modifications can elongate or desaturate fatty acids. The end products are typically long-chain fatty acids that are esterified into triglycerides for storage in adipose tissue or exported as part of very-low-density lipoproteins (VLDL) by the liver.

Regulation of lipogenesis is tightly controlled by hormonal and nutrient signals. Insulin promotes lipogenesis by increasing transcription of lipogenic enzymes (via SREBP-1c and ChREBP) and by stimulating ACC activity, while glucagon and epinephrine inhibit it. Citrate and allosteric activation of ACC, and AMP-activated protein kinase–mediated inhibition, modulate the flow of carbon toward fatty acid synthesis. Malonyl-CoA also inhibits fatty acid oxidation by restricting mitochondrial entry of fatty acids.

Physiologically, lipogenesis supports energy storage and membrane biogenesis. Excess lipogenesis can contribute to metabolic disorders such as non-alcoholic fatty liver disease and obesity when coupled with impaired fatty acid oxidation or high caloric intake.