Are Fatty Acids Gluconeogenic Precursors?

Abstract

It is widely accepted that the tricarboxylic acid (TCA) cycle is a critical partner for gluconeogenesis (GNG) in hepatocytes. Although researchers in the 1950s showed, using radiolabeled long-chain fatty acids, that acetate derived from fatty acid β-oxidation contributes carbon to glucose, fatty acids are not included on lists of gluconeogenic precursors in many textbooks of biochemistry and nutritional biochemistry. Here, by following the flow of carbon atoms through the mitochondrial TCA cycle and into cytosolic GNG, it is shown that carbons in acetyl-CoA derived from fatty acid β-oxidation will be found in glucose. Specifically, it is evident that, after the condensation of acetyl-CoA and oxaloacetate (OAA) to make citrate at the start of the TCA cycle, the 2 carbons lost from the cycle as carbon dioxide come from OAA, not acetyl-CoA. Carbons from acetyl-CoA are retained as the cycle progresses toward malate, and when malate exits the mitochondrion for GNG, carbons that originated in acetyl-CoA and OAA are found to contribute equally to glucose. With influx of other critical precursors into the TCA cycle and efflux of malate into the cytosol for GNG, the TCA cycle is in balance. During fasting-induced GNG, there is a net gain of glucose in glucogenic cells; however, the fact that there is no net gain in the TCA cycle is irrelevant as far as precursors are concerned. Given the physiological importance of fat as a source of reserve energy, and knowing that some cell types rely on glucose as their primary supplier of energy, a role for fatty acids in glucose production aligns both with intuition and with evidence provided by a careful look at the biochemistry and older isotope studies. Hopefully, subsequent editions of textbooks will list fatty acids among the gluconeogenic precursors.