Regulation of lipid metabolism

The release of fatty acids from adipose tissue is regulated by the rate of hydrolysis of triacylglycerol and the rate of esterification of acyl-CoA with glycerol 3-phosphate. The rate of hydrolysis is stimulated by hormones that bind to cell-surface receptors and stimulate adenylate cyclase (which catalyzes the production of cAMP from ATP). Hormone-sensitive lipase (Sec. 13.4) can exist in two forms, one of which exhibits very low activity and a second which is phosphorylated and has high activity. Before hormonal stimulation of adenylate cyclase, the low-activity lipase predominates in the fat cell. Stimulation of protein kinase by an increase in cAMP concentration leads to phosphorylation of the low-activity lipase. An increase in the rate of hydrolysis of triacylglycerol and the release of fatty acids from the fat cell follows. This leads to a greater utilization of fatty acids by tissues such as heart, skeletal muscle, and liver. 

In liver, /3-oxidation and reesterification of acyl-CoA are both possible. The rate of /3-oxidation is determined initially by the rate at which acyl groups enter the mitochondrial matrix. This rate of entry may be decreased by malonyl-CoA, which inhibits carnitine palmitoyltransferase (an enzyme 

Insulin is an antilipolytic hormone, and its effect on adipose tissue is to increase the transport of glucose into the fat cell, to stimulate lipogenesis and inhibit lipolysis. Thus, pyruvate dehydrogenase and acetyl-CoA carboxylase are activated, and the hormone-sensitive lipase is inactivated. In the normal, well-fed state insulin stimulates the deposition of fat. 

Insulin also exerts a stimulatory effect on the synthesis of cholesterol in the liver. In this tissue, HMG-CoA reductase is activated. HMG-CoA reductase, like hormone-sensitive lipase, can exist in two forms one is phosphorylated (inactive) and the other is dephosphorylated (active). Phosphorylation of the enzyme depends on an increase in the cellular concentration of cAMP and activation of protein kinase. The dephosphorylation (activation) is catalyzed by a phosphatase. In fat cells, a similar phosphatase dephosphorylates (inactivates) hormone-sensitive lipase. Insulin stimulates the activity of the phosphatase in both liver and fat cells. In this way, active HMG-CoA reductase predominates in the liver cell and directs HMG-CoA into cholesterol synthesis, and in the fat cell hormone-sensitive lipase is inactivated. 

What are the consequences of abnormal deconjugation of bile salts by bacteria in the small intestine  

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Peroxisome-proliferator activated receptors (PPARs) are lipid-activated transcription factors exerting several functions in development and metabolism. PPARa is implicated in the regulation of lipid metabolism, lipoprotein synthesis, and inflammatory response in liver and other tissues. 

The best-known effect of APOE is the regulation of lipid metabolism (see Fig. 10.13). APOE is a constituent of TG-rich chylomicrons, VLDL particles and their remnants, and a subclass of HDL. In addition to its role in the transport of cholesterol and the metabolism of lipoprotein particles, APOE can be involved in many other physiological and pathological processes, including immunoregu-lation, nerve regeneration, activation of lipolytic enzymes (hepatic lipase, lipoprotein lipase, lecithin cholesterol acyltransferase), ligand for several cell receptors, neuronal homeostasis, and tissue repair (488,490). APOE is essential... 

Esau C, Davis S, Murray SF et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. CellMetab 2006 3 87-98. 

Langrn, D., Holm, C., Lafontan, M. (1996) Adipocyte hormone-sensitive lipase a major regulator of lipid metabolism. Proc. Nutr. Soc. 55, 93-109. 

Understand hormonal regulation of lipid metabolism, and for each metabolic pathway, be able to identify the rate-controlling step and its mode of regulation. 

Figure 19.12 Regulation of liver acetyl-CoA carboxylase and cholesterol biosynthesis by phosphorylation. ACC indicates acetyl-CoA carboxylase. Bold arrow indicates activation of kinase kinase by fatty acyl-CoA. (Reproduced by permission from Hardie DG, Carling D, Sim ATR. The AMP-activated protein kinase a multi-substrate regulator of lipid metabolism. Trends Biochem Sci 14 20-23, 1989.)...

Hardie DG, Carling D, Sim ATR. The AMP-activated protein kinase a multisubstrate regulator of lipid metabolism. Trends Biochem Sci January 20, 1989. 

The liver also plays a central role in the regulation of lipid metabolism. When fuels are abundant, fatty acids derived from the diet or synthesized by the liver are esterified and secreted into the blood in the form of very low density lipoprotein (see Figure 30.15). However, in the fasting state, the liver converts fatty acids into ketone bodies. How is the fate of liver fatty acids determined The selection is made according to whether the fatty acids enter the mitochondrial... 

The liver synthesizes two enzymes involved in intra-plasmic lipid metabolism hepatic triglyceride lipase (HTL) and lecithin-cholesterol-acyltransferase (LCAT). The liver is further involved in the modification of circulatory lipoproteins as the site of synthesis for cholesterol-ester transfer protein (CETP). Free fatty acids are in general potentially toxic to the liver cell. Therefore they are immobilized by being bound to the intrinsic hepatic fatty acid-binding protein (hFABP) in the cytosol. The activity of this protein is stimulated by oestrogens and inhibited by testosterone. Peripheral lipoprotein lipase (LPL), which is required for the regulation of lipid metabolism, is synthesized in the endothelial cells (mainly in the fatty tissue and musculature). 

Liver X receptors (LXRs) are nuclear receptors involved in the regulation of lipid metabolism and inflammatory responses in the CNS [440], LXR agonists induce the transcriptional activity of LXR target genes, attenuating the imbalance of cholesterol metabolism and overactivation of microglia and astrocytes in inflammation [441],... 

Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, Watts L, Booten SL, Graham M, McKay R, Subramaniam A, Propp S, Lollo BA, Freier S, Bennett CF, Bhanot S, Monia BP (2006) miR-122 regulation of lipid metabolism revealed by in vivo anti-sense targeting. Cell Metab 3(2) 87-98. doi 10.1016/j.cmet.2006.01.005... 

Regulation of Hptt metabolism Regulation of lipid metabolism by niacin and isoprenaiine... 

Nakamura, K., Moore, R., Negishi, M., and Sueyoshi, T. (2007) Nuclear pregnane X receptor cross-talk with FoxA2 to mediate drug-induced regulation of lipid metabolism in fasting mouse liver. J. Biol. Chem. 282, 9768-9776. 

The AMP-activated proteinkinase A multi substrate regulator of lipid metabolism, D. G. Hardie, D. Carling, and A. 

Novel Proteins That Regulate Sphingolipid Synthesis Could Affect the Regulation of Lipid Metabolism... 

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