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Fatty Acid SynthesisEdit

Fatty acid synthesis, often called de novo lipogenesis, is the cellular process by which cells convert acetyl-CoA into fatty acids in the cytosol. In humans, the liver is the primary site of this synthesis, with contributions from adipose tissue and other organs under certain nutritional states. The main end product is palmitic acid (C16:0), which can be elongated or desaturated to yield other fatty acids that populate phospholipids, triglycerides, and other lipid pools. The pathway relies on NADPH as a reducing agent and is tightly regulated by hormonal signals, nutrient availability, and cellular energy status. It serves as a crucial link between carbohydrate metabolism and lipid storage, enabling the body to store excess energy efficiently when calories are abundant. acetyl-CoA NADPH lipogenesis

Biochemical pathway

  • Overview of the basic flow
    • Fatty acid synthesis begins with acetyl-CoA in the cytosol, which is derived from mitochondrially produced acetyl-CoA via the citrate shuttle. Citrate is exported to the cytosol and cleaved back into acetyl-CoA and oxaloacetate by ATP citrate lyase.
    • The committed, rate-limiting step is the carboxylation of acetyl-CoA to malonyl-CoA by acetyl-CoA carboxylase (ACC). Malonyl-CoA then serves as the two-carbon donor in successive condensations that build the growing fatty acyl chain on the multifunctional enzyme complex fatty acid synthase (FAS).
    • Each cycle adds two carbons to the growing chain, using NADPH as the reducing power, until a saturated 16-carbon fatty acid (palmitoyl-CoA) is produced. Further elongation and desaturation of fatty acids are carried out by elongase enzymes and desaturase enzymes, respectively.
    • Palmitoyl-CoA can be incorporated into glycerolipids to form triglycerides or phospholipids, or it can be released as a fatty acid when needed. The process is linked to other metabolic routes, including β-oxidation when energy is required, and is intertwined with carbohydrate flux through glycolysis and the pentose phosphate pathway.
  • Key enzymes and substrates
    • ACC responsible for malonyl-CoA production; FAS as the core biosynthetic machine; NADPH as the electron donor; citrate as a signal and substrate for cytosolic acetyl-CoA production; intermediates such as malonyl-CoA regulate other pathways, including the entry of fatty acids into mitochondria via CPT1.
    • For a more complete view of the components, see acetyl-CoA carboxylase, fatty acid synthase, NADPH, and CPT1.

Regulation

  • Hormonal control
    • Insulin is a primary activator of lipogenesis in the liver and adipose tissue, promoting transcription of lipogenic genes and activating ACC and FAS. In contrast, glucagon and epinephrine suppress fatty acid synthesis during fasting or stress.
  • Allosteric and metabolic signals
    • Citrate that accumulates in the cytosol activates ACC, signaling abundant energy supply and substrate readiness for fatty acid synthesis.
    • Malonyl-CoA, the product of ACC, inhibits mitochondrial fatty acid entry by restraining CPT1, coordinating lipid synthesis with the restriction of fatty acid oxidation when energy is plentiful.
  • Transcriptional regulation
    • Transcription factors such as SREBP-1c and ChREBP drive the expression of lipogenic enzymes in response to dietary and hormonal cues, linking nutrient status to enzyme abundance.
  • Tissue specificity
    • The liver and adipose tissue are the principal sites of de novo lipogenesis in humans, but other tissues can contribute under certain conditions. The balance among tissues reflects metabolic state, dietary intake, and genetic background.
  • Nutritional and dietary influences
    • High carbohydrate intake, particularly refined sugars, can upregulate de novo lipogenesis, whereas diets rich in fats can shift substrate utilization. The precise contribution of DNL to total hepatic lipid pools varies with diet and physiology.

Physiological role and clinical considerations

  • Physiological role
    • De novo lipogenesis converts excess caloric carbohydrates into fatty acids for storage as triglycerides, providing a means to store energy for future use. This pathway also supplies lipid precursors for membrane synthesis and signaling molecules.
  • Health and metabolic implications
    • Persistent upregulation of lipogenesis can contribute to hepatic steatosis in the context of overnutrition, obesity, or insulin resistance. Non-alcoholic fatty liver disease (NAFLD) is linked to imbalanced lipid handling in the liver and adipose tissue.
    • The relative contribution of DNL to circulating triglycerides and hepatic fat varies among individuals and populations. In some dietary patterns, DNL accounts for a modest fraction of hepatic fatty acids, while in others it becomes more prominent when carbohydrate intake is high.
  • Therapeutic and dietary considerations
    • Understanding the lipogenic pathway has implications for treating metabolic diseases. Experimental inhibitors of ACC and other lipogenic enzymes have been studied, while dietary strategies focus on balanced macronutrient intake and energy homeostasis. See NAFLD for a disease framework and lipid metabolism for broader context.

Evolution, diversity, and physiology across species

  • Lipogenesis is a conserved metabolic capability across vertebrates, but its relative importance and regulation differ by species, diet, and ecological niche. In some species, dietary fat plays a larger role in energy storage, whereas in others, rapid carbohydrate flux can drive substantial lipogenesis. The enzymes involved, including FASN and the acetyl-CoA carboxylase family, show conserved motifs but can be tuned to tissue-specific needs and dietary environments.

Controversies and debates

  • Debates about the role of de novo lipogenesis in obesity and metabolic disease reflect broader disagreements about diet and public health policy.
    • A key point of contention is how much DNL contributes to hepatic lipid accumulation in modern diets. Some researchers emphasize that high carbohydrate intake, especially fructose-containing sugars, can drive DNL and thereby contribute to NAFLD, while others argue that dietary fat intake and adipose tissue lipolysis are the dominant sources of fatty acids for the liver in most people.
    • These disagreements have policy implications. Proponents of simple, universal dietary rules argue for straightforward messaging and broad strategies like sugar reduction or labeling, while others caution that nutrition science is nuanced and that one-size-fits-all prescriptions can be ineffective or counterproductive.
  • From a market-oriented, individual-responsibility perspective, the best approach is evidence-based policy that emphasizes transparent information, personal choice, and incentives for healthier options rather than broad mandates. Critics of blanket dietary restrictions warn that moralizing nutrition can distort science, stigmatize food choices, and undercut practical, targeted interventions.
  • Critics sometimes describe liberal or moralizing rhetoric about nutrition as overreaching or counterproductive. A balanced view, however, acknowledges that public health guidance should be rooted in robust evidence, account for heterogeneity across populations, and avoid conflating health advice with moral judgments about personal behavior.

See also