Lipogenesis
Lipogenesis is the de novo synthesis of fatty acids from acetyl-CoA precursors, primarily in fed states, involving sequential carboxylation, condensation, reduction, dehydration, and elongation cycles to produce palmitate (C16:0), which is then esterified into triglycerides.
Detailed Biochemical Pathway Steps
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Citrate shuttle and acetyl-CoA generation: Mitochondrial citrate (from citrate synthase) exits via the tricarboxylate carrier, entering cytosol where ATP-citrate lyase (ACLY) cleaves it: citrate + ATP + CoA → acetyl-CoA + oxaloacetate + ADP + Pi. Oxaloacetate reduces to malate via cytosolic MDH, decarboxylates via malic enzyme to pyruvate (generating NADPH), and re-enters mitochondria.
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Malonyl-CoA formation (committed step): Acetyl-CoA carboxylase (ACC1) carboxylates acetyl-CoA to malonyl-CoA: acetyl-CoA + HCO₃⁻ + ATP → malonyl-CoA + ADP + Pi. Biotin shuttles CO₂; Mg²⁺ stabilizes; allosteric citrate activates, while malonyl-CoA/AMPK inhibits.
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Fatty acid synthase (FASN) cycles (seven iterations for palmitate):
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Priming: Acetyl-CoA:ACP transacylase loads acetyl onto phosphopantetheine (pantetheine arm of ACP).
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Malonyl loading: Malonyl-CoA:ACP transacylase transfers malonyl to ACP.
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Condensation: β-ketoacyl synthase (KS) decarboxylates malonyl-ACP, condenses with acetyl/malonyl unit: → acetoacetyl-ACP (C4 β-ketoacyl).
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Reduction: β-ketoacyl reductase (KR) uses NADPH: β-keto → β-hydroxyacyl-ACP.
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Dehydration: β-hydroxyacyl dehydratase (DH): → crotonyl-ACP (trans-Δ²-enoyl).
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Enoyl reduction: Enoyl reductase (ER) uses NADPH: → butyryl-ACP (C4 saturated).
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Transfer butyryl to KS cysteine; repeat with new malonyl for C6, C8, etc., up to C16 (palmitoyl-ACP). Thioesterase hydrolyzes palmitate.
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Post-synthesis modification and storage: Palmitate elongates via ER (ELOVL1-7) in ER, desaturates (SCD1 Δ9), activates to palmitoyl-CoA, and assembles triglycerides on glycerol-3-P: GPAT (mito/ER) → LPA; AGPAT → PA; lipin phosphatidic acid phosphatase → DAG; DGAT → TAG for lipid droplets.
Regulatory Mechanisms and Pathophysiology
Insulin via SREBP-1c/ChREBP transcriptionally upregulates ACLY/ACC/FASN; mTORC1 phosphorylates lipin-1 for nuclear exclusion, favoring lipogenesis. AMPK phosphorylates ACC (Ser79/212, inactivating); PUFAs inhibit via Insig-SREBP retention. Dysregulation in NAFLD elevates DNL (de novo lipogenesis) >25% of hepatic lipids, fueling steatosis via fructose-ChREBP. Inhibitors like FASN allosteric (TVB-2640) or ACLY (bempedoic acid) mitigate cardiometabolic risks.