Comprehensive Physiology Wiley Online Library

Regulation of Ketogenesis in Liver

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Roles of Insulin and Glucagon in Substrate Supply for Hepatic Ketogenesis
2 Effects of Ketones on the Endocrine Pancreas and Adipose Tissue
3 Intrahepatic Partitioning of Fatty Acids Between Oxidation and Esterification
3.1 Pancreatic Hormone Effects on Enzyme Substrate Availability
3.2 Expression of Enzyme Activity
3.3 Role of Malonyl CoA
3.4 Role of Carnitine Palmitoyltransferase I Membrane Topology and Membrane‐Protein Interactions
3.5 Control of Carnitine Palmitoyltransferase I over Ketogenesis: Effects of Altered Insulin Status
3.6 In Vivo Monitoring of Hepatic Acyl‐CoA Partitioning
4 Intramitochondrial Regulation of Ketogenesis
4.1 Modulation of Mitochondrial 3‐Hydroxy‐3‐Methylglutaryl‐CoA Synthase Activity
4.2 Examples of Physiological Conditions Involving Pancreatic Hormone Regulation of Ketogenesis
5 General Comments
Figure 1. Figure 1.

Pathway leading from entry of long‐chain fatty acids into liver cells to formation of ketone bodies, showing the two major branch points involved in determining the fats of cytosolic acyl CoA and intramitochondrial acetyl CoA. The relationship between fatty acid synthesis and oxidation, mediated through inhibition of carnitine palmitoyltransferase I (CPT I) by malonyl CoA, is also shown. GPAT, glycerol‐3‐phosphate acyltransferase; C‐ACT, carnitine‐acylcarnitine translocase; FA, Fatty Acids; HMG, 3‐hydroxy‐3‐methylglutaryl.

Figure 2. Figure 2.

Complex interactions between the effects of insulin and glucagon mediated through their effects on hepatic malonyl‐CoA levels (through their action on acetyl‐CoA carboxylase, ACC) and on mitochondrial (mito) glycerol‐3‐phosphate acyltransferase (GPAT) and mitochondrial β oxidation, respectively. er, endoplasmic reticulum; CPT‐I carnitine palmitoyltransferase I.

Figure 3. Figure 3.

Effects of elevated insulin/glucagon molar concentrations on metabolism of fatty acids (FA), triacylglycerols (TAG), and ketone bodies in vivo. In insulin‐resistant states, the effects of insulin on all three tissues are blunted, resulting in chronically elevated plasma non‐esterified fatty acids (NEFA) and increased triacylglycerol secretion and mitochondrial β‐oxidation of fatty acids in liver. VLDL, very‐low‐density lipoproteins. Fluxes of substrates between tissues are denoted by solid lines. Regulatory interactions are denoted by broken lines. The effect of insulin on hepatic triacylglycerol secretion is bi‐direction, depending on the physiological state: stimulatory in normoinsulinaemic and inhibitory in hypo‐insulinaemic states [142].



Figure 1.

Pathway leading from entry of long‐chain fatty acids into liver cells to formation of ketone bodies, showing the two major branch points involved in determining the fats of cytosolic acyl CoA and intramitochondrial acetyl CoA. The relationship between fatty acid synthesis and oxidation, mediated through inhibition of carnitine palmitoyltransferase I (CPT I) by malonyl CoA, is also shown. GPAT, glycerol‐3‐phosphate acyltransferase; C‐ACT, carnitine‐acylcarnitine translocase; FA, Fatty Acids; HMG, 3‐hydroxy‐3‐methylglutaryl.



Figure 2.

Complex interactions between the effects of insulin and glucagon mediated through their effects on hepatic malonyl‐CoA levels (through their action on acetyl‐CoA carboxylase, ACC) and on mitochondrial (mito) glycerol‐3‐phosphate acyltransferase (GPAT) and mitochondrial β oxidation, respectively. er, endoplasmic reticulum; CPT‐I carnitine palmitoyltransferase I.



Figure 3.

Effects of elevated insulin/glucagon molar concentrations on metabolism of fatty acids (FA), triacylglycerols (TAG), and ketone bodies in vivo. In insulin‐resistant states, the effects of insulin on all three tissues are blunted, resulting in chronically elevated plasma non‐esterified fatty acids (NEFA) and increased triacylglycerol secretion and mitochondrial β‐oxidation of fatty acids in liver. VLDL, very‐low‐density lipoproteins. Fluxes of substrates between tissues are denoted by solid lines. Regulatory interactions are denoted by broken lines. The effect of insulin on hepatic triacylglycerol secretion is bi‐direction, depending on the physiological state: stimulatory in normoinsulinaemic and inhibitory in hypo‐insulinaemic states [142].

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Victor A. Zammit. Regulation of Ketogenesis in Liver. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 659-673. First published in print 2001. doi: 10.1002/cphy.cp070221