Short- & Long-Term Mechanisms Regulate Lipogenesis
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p230-232
2025-07-16
366
Long-chain fatty acid synthesis is controlled in the short term by allosteric and covalent modification of enzymes and in the long term by changes in gene expression governing rates of synthesis of enzymes.
Acetyl-CoA Carboxylase Is the Most Important Enzyme in the Regulation of Lipogenesis
Acetyl-CoA carboxylase is an allosteric enzyme and is activated by citrate, which increases in concentration in the well-fed state and is an indicator of a plentiful supply of acetyl CoA. Citrate promotes the conversion of the enzyme from an inactive dimer (two subunits of the enzyme complex) to an active polymeric form, with a molecular mass of several million. Inactivation is promoted by phosphorylation of the enzyme and by long-chain acyl-CoA molecules, an example of negative feedback inhibition by a product of a reaction (Figure 1). Thus, if acyl-CoA accumulates because it is not esterified quickly enough or because of increased lipolysis or an influx of free fatty acids into the tissue, it will automatically reduce the rate of synthesis of new fatty acid. Acyl-CoA also inhibits the mitochondrial tricarboxylate transporter, thus preventing activation of the enzyme by egress of citrate from the mitochondria into the cytosol (see Figure 1).
Fig1. Regulation of acetyl-CoA carboxylase. Acetyl CoA carboxylase is activated by citrate, which promotes the conversion of the enzyme from an inactive dimer to an active polymeric form. Inactivation is promoted by phosphorylation of the enzyme and by long-chain acyl-CoA molecules such as palmitoyl-CoA. In addition, acyl-CoA inhibits the tricarboxylate transporter, which trans ports citrate out of mitochondria into the cytosol, thus decreasing the citrate concentration in the cytosol and favoring inactivation of the enzyme.
Acetyl-CoA carboxylase is also regulated by hormones such as glucagon, epinephrine, and insulin via changes in its phosphorylation state (details in Figure 2).
Fig2. Regulation of acetyl-CoA carboxylase by phosphorylation/dephosphorylation. The enzyme is inactivated by phosphorylation by AMP-activated protein kinase (AMPK), which in turn is phosphorylated and activated by AMP-activated protein kinase kinase (AMPKK). Glucagon and epinephrine increase cAMP, and thus activate this latter enzyme via cAMP-dependent protein kinase. The kinase kinase enzyme is also believed to be activated by acyl-CoA. Insulin activates acetyl-CoA carboxylase via dephosphorylation of AMPK.
Pyruvate Dehydrogenase Is Also Regulated by Acyl-CoA
Acyl-CoA causes an inhibition of pyruvate dehydrogenase, the enzyme which catalyzes the formation of acetyl-CoA from pyruvate to link glycolysis with the citric acid cycle, by inhibiting the ATP-ADP exchange transporter of the inner mitochondrial membrane. This leads to increased intramitochondrial (ATP)/(ADP) ratios and therefore to conversion of active to inactive pyruvate dehydrogenase, thus regulating the availability of acetyl-CoA for lipogenesis. Furthermore, oxidation of acyl CoA due to increased levels of free fatty acids may increase the ratios of (acetyl-CoA)/(CoA) and (NADH)/(NAD+) in mitochondria, which also inhibits pyruvate dehydrogenase.
Insulin Also Regulates Lipogenesis by Other Mechanisms
Insulin stimulates lipogenesis by several other mechanisms as well as by increasing acetyl-CoA carboxylase activity. It increases the transport of glucose into the cell (eg, in adipose tissue), increasing the availability of both pyruvate (and thus acetyl-CoA) for fatty acid synthesis and glycerol-3-phosphate for triacylglycerol synthesis via esterification of the newly formed fatty acids, and also converts the inactive form of pyruvate dehydrogenase to the active form in adipose tissue, although not in liver. Insulin also-by its ability to depress the level of intracellular cAMP-inhibits lipolysis in adipose tissue, reducing the concentration of plasma-free fatty acids and, therefore, long-chain acyl-CoA, which are inhibitors of lipogenesis.
The Fatty Acid Synthase Complex & Acetyl-CoA Carboxylase Are Adaptive Enzymes
These enzymes adapt to the body’s physiologic needs via changes in gene expression which lead to increases in the total amount of enzyme protein present in the fed state and decreases during intake of a high-fat diet and in conditions such as starvation, and diabetes mellitus. Insulin plays an important role, promoting gene expression and induction of enzyme biosynthesis, and glucagon (via cAMP) antagonizes this effect. Feeding fats containing polyunsaturated fatty acids coordinately regulates the inhibition of expression of key enzymes of glycolysis and lipogenesis. These mechanisms for longer-term regulation of lipogenesis take several days to become fully manifested and augment the direct and immediate effect of free fatty acids and hormones such as insulin and glucagon.
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