Ketone bodies regulation

McGarry, J. D., and Foster, D. W., 1980. Regulation of hepatic fatty acid oxidation and ketone body production. Annual Review of Biochemistry 49 395-420. 

After uptake by the liver, free fatty acids are either P Oxidized to COj or ketone bodies or esterified to triacylglycerol and phospholipid. There is regulation of entry of fatty acids into the oxidative pathway by carnitine palmitojdtransferase-I (CPT-I), and the remainder of the fatty acid uptake is esterified. CPT-I activity is... 

Two conditions in which the rate of ketone body formation is increased are hypoglycaemia and prolonged starvation in adults or short-term starvation in children. What is the mechanism for increasing the rate Although there are several fates for fatty acids in the liver, triacylglycerol, phospholipid and cholesterol formation and oxidation via the Krebs cycle, the dominant pathway is ketone body formation (Figure 7.20). Three factor regulate the rate of ketone body formation (i) hormone sensitive lipase activ-... 

These changes provide further biochemical support for the mechanisms proposed for regulation of ketone body synthesis that are discnssed above. 

The effects of the glucose/fatty acid cycle and those of the hormones on the cycle, on the regulation of the blood glucose level, can be extended by two further changes in metabolism, (i) Fatty acids are taken up by hver and converted to ketone bodies, which are released... 

Formation of mevalonate. The conversion of acetyl CoA to acetoacetyl CoA and then to 3-hydroxy-3-methylglutaryl CoA (3-HMG CoA) corresponds to the biosynthetic pathway for ketone bodies (details on p. 312). In this case, however, the synthesis occurs not in the mitochondria as in ketone body synthesis, but in the smooth endoplasmic reticulum. In the next step, the 3-HMG group is cleaved from the CoA and at the same time reduced to mevalonate with the help of NADPH+H 3-HMG CoA reductase is the key enzyme in cholesterol biosynthesis. It is regulated by repression of transcription (effectors oxysterols such as cholesterol) and by interconversion... 

FIGURE 21-19 Regulation of triacylglycerol synthesis by insulin. Insulin stimulates conversion of dietary carbohydrates and proteins to fat. Individuals with diabetes mellitus lack insulin in uncontrolled disease, this results in diminished fatty acid synthesis, and the acetyl-CoA arising from catabolism of carbohydrates and proteins is shunted instead to ketone body production. People in severe ketosis smell of acetone, so the condition is sometimes mistaken for drunkenness (p. 909). 

DNA replication, RNA, genes, exons, introns, cloning Transcription and translation Gene regulation, mutation, recombinant DNA Cells, mitochondria, common catabolic pathway Phosphorylation, energy yield, conversion Glycosis, energy yield, catabolism Ketone bodies, catabolism Fourth hour exam... 

Primary carnitine deficiency is caused by a deficiency in the plasma-membrane carnitine transporter. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for p oxidation and energy production, and the production of ketone bodies (which are used by the brain) is also impaired. Regulation of intramitochondrial free CoA is also affected, with accumulation of acyl-CoA esters in the mitochondria. This in turn affects the pathways of intermediary metabolism that require CoA, for example the TCA cycle, pyruvate oxidation, amino acid metabolism, and mitochondrial and peroxisomal -oxidation. Cardiac muscle is affected by progressive cardiomyopathy (the most common form of presentation), the CNS is affected by encephalopathy caused by hypoketotic hypoglycaemia, and skeletal muscle is affected by myopathy. 

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 regulation of fatty acid oxidation, fatty acid synthesis and ketone body synthesis in the liver is summarized in fig. 10.10 ... 

Regulation of insulin secretion is affected by numerous factors, such as ftKxl, hormonal and neuronal stimuli, and innic mechanisms. In humans, the principal sub.slratc that stimulates the release of in.sulin from the islet /3-cells is glucose. In addition to glucose, other substrates (c.g., amino acids, free fatty acids, and ketone bodies) also can stimulate insulin. secretion directly. Secretin and ACTH can directly stimulate insulin secretion. Glucagon and other related peptides can increase the secretion of insulin, whereas somatostatin inhibits its secretion. 

D. In the synthesis of cholesterol, but not of ketone bodies, HMG CoA is reduced by NADPH + H+ to mevalonic add. The enzyme, HMG CoA reductase, is highly regulated (it is inhibited by cholesterol and bile salts and induced by insulin). Mevalonic acid is converted to isopentenyl pyrophosphate, which provides isoprenoid units for the synthesis of cholesterol and its derivatives and for many other compounds. 

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