Glucagon fatty acid metabolism

Glucagon, whose regulalory crfect on carbohydrate and fatty acid metabolism is well understood, is therapeutically important. It is recommended for the treatment of severe hypoglycemic reactions cau.sed by the administration of in-.sulin to diabetic or psychiatric patients. Of course, this treatment is effective only when hepatic glycogen is available. Nausea and vomiting are the most frequently encountered reactions to glucagon. 

Between meals, a decreased insulin level and increased levels of insulin counter-regulatory hormones (e.g., glucagon) activate hpolysis, and free fatty acids are transported to tissues bound to serum albumin. Within tissnes, energy is derived from oxidation of fatty acids to acetyl CoA in the pathway of -oxidation. Most of the enzymes involved in fatty acid oxidation are present as 2-3 isoenzymes, which have different but overlapping specificities for the chain length of the fatty acid. Metabolism of unsaturated fatty acids, odd-chain-length fatty acids, and medium-chain-length fatty acids requires variations of this basic pattern. The acetyl CoA produced from fatty acid oxidation is principally oxidized in the TCA cycle or converted to ketone bodies in the liver. 

Figure 25-7. Metabolism of adipose tissue. Hormone-sensitive lipase is activated by ACTH, TSH, glucagon, epinephrine, norepinephrine, and vasopressin and inhibited by insulin, prostaglandin E, and nicotinic acid. Details of the formation of glycerol 3-phosphate from intermediates of glycolysis are shown in Figure 24-2. (PPP, pentose phosphate pathway TG, triacylglycerol FFA, free fatty acids VLDL, very low density lipoprotein.)...

In adipose tissue, the effect of the decrease in insulin and increase in glucagon results in inhibition of lipo-genesis, inactivation of lipoprotein lipase, and activation of hormone-sensitive lipase (Chapter 25). This leads to release of increased amounts of glycerol (a substrate for gluconeogenesis in the liver) and free fatty acids, which are used by skeletal muscle and liver as their preferred metabolic fuels, so sparing glucose. 

The regulation of fat metabolism is relatively simple. During fasting, the rising glucagon levels inactivate fatty acid synthesis at the level of acetyl-CoA carboxylase and induce the lipolysis of triglycerides in the adipose tissue by stimulation of a hormone-sensitive lipase. This hormone-sensitive lipase is activated by glucagon and epinephrine (via a cAMP mechanism). This releases fatty acids into the blood. These are transported to the various tissues, where they are used. 

Dysfunction of fat metabolism is caused by the low insulin/glucagon ratio, which stimulates fat mobilization by adipose tissue, flooding the liver with fatty acids and raising intracellular acetyl CoA levels. 

Effects on lipid metabolism Glucagon favors hepatic oxidation of fatty acids and the subsequent formation of ketone bodies fan acetyl CoA. The lipolytic effect of glucagon in adipose tissue is minimal in humans. 

CM and VLDL secreted by intestinal cells and VLDL synthesized and secreted in the liver have similar metabolic fates. After secretion into the blood, newly formed CM and VLDL take up apoprotein (apo-C) from HDL and are subsequently removed from the blood (plasma half-life of less than 1 h in humans [137]) primarily by the action of lipoprotein lipase (LPL). Lipoprotein lipase is situated mainly in the vascular bed of the heart, skeletal muscle, and adipose tissue and catalyzes the breakdown of core TG to monoglycerides and free fatty acids, which are taken up into adjacent cells or recirculated in blood bound to albumin. The activity of LPL in the heart and skeletal muscle is inversely correlated with its activity in adipose tissue and is regulated by various hormones. Thus, in the fasted state, TG in CM and VLDL is preferentially delivered to the heart and skeletal muscle under the influence of adrenaline and glucagon, whereas in the fed state, insulin enhances LPL activity in adipose tissue, resulting in preferential uptake of TG into adipose tissue for storage as fat. 

Glucagon affects hepatic lipid metabolism. A major effect is inhibition of fatty acid synthesis, which is mainly due to the phosphorylation and inhibition of acetyl-GoA carboxylase by cAMP-dependent protein kinase. ATP-citrate lyase is also phosphorylated, but it is unclear that this is involved in the inhibition of lipogene-sis. Glucagon also inhibits cholesterol synthesis apparently due to a decrease in the activity of hydroxymethylglutaryl-CoA reductase. This is thought to result from a decrease in the activity of protein phosphatase I due to the increased phosphorylation and activation of a heat stable inhibitor by cAMP-dependent protein kinase. This mechanism could also contribute to the effects of glucagon on other hepatic enzymes. 

FFA, free fatty acid GH, growth hormone GLP-1, glucagon-like protein 1 GS, glycogen synthase GSK3, glycogen synthase kinase 3 HDL, high density lipoprotein HF, heart failure IKK, inhibitor of kappa B kinase INK, c-jun N-terminal kinase EDL, low density lipoprotein Ep(a), lipoprotein little a EV, left ventricular MetS, metabolic syndrome MI, myocardial infarction... 

Ketogenesis is an important metabolic function in the liver. It is the result of an increase in lipolysis in the fatty tissue, with a rise in fatty acids. Insulin inhibits ketogenesis, whereas it is accelerated by fasting as well as by glucagons and insulin deficiency. Ketones (acetacetate, 3-hydroxybutyrate, acetone) are synthesized by means of P-oxidation from acetyl-CoA, assuming the production of this substance exceeds the amount required by the hepa-tocytes (and glucose metabolism is simultaneously reduced). The liver itself does not require any ketones acetone is expired, whereas 3-hydroxybutyrate and acetacetate serve as a source of energy. Ketonaemia can lead to metabolic acidosis and electrolyte shifts. 

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