Fatty acid metabolism lipolysis

Insulin resistance occurs when the normal response to a given amount of insulin is reduced. Resistance of liver to the effects of insulin results in inadequate suppression of hepatic glucose production insulin resistance of skeletal muscle reduces the amount of glucose taken out of the circulation into skeletal muscle for storage and insulin resistance of adipose tissue results in impaired suppression of lipolysis and increased levels of free fatty acids. Therefore, insulin resistance is associated with a cluster of metabolic abnormalities including elevated blood glucose levels, abnormal blood lipid profile (dyslipidemia), hypertension, and increased expression of inflammatory markers (inflammation). Insulin resistance and this cluster of metabolic abnormalities is strongly associated with obesity, predominantly abdominal (visceral) obesity, and physical inactivity and increased risk for type 2 diabetes, cardiovascular and renal disease, as well as some forms of cancer. In addition to obesity, other situations in which insulin resistance occurs includes... 

The neurohormonal control of lipid metabolism chiefly affects the mobilization and synthesis of triglycerides in the fat tissue. The lipolysis in tissues is dependent upon the activity of triglyceride lipase. All the regulators that favour the conversion of the inactive (nonphosphorylated) lipase to the active (phosphoiylated) one, stimulate the lipolysis and the release of fatty acids into the blood. Adrenalin... 

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. 

Figure 16.3 Effects of insulin on the glucose/fatty acid cycle. Insulin enhances glucose metabolism by stimulating glucose uptake by muscle and adipose tissue and by inhibiting lipolysis in adipose tissue (see Chapter 12 for the mechanism of these effects). The effect of glucose metabolism on lipolysis is via stimulation of fatty acid esterification via glycerol 3-phosphate.

Metabolic effects. P-Receptors mediate increased conversion of glycogen to glucose (glycogenolysis) in both liver and skeletal muscle. From the liver, glucose is released into the blood. In adipose tissue, triglycerides are hydrolyzed to fatty acids lipolysis, mediated by P3-receptors), which then enter the blood (C). The metabolic effects of catecholamines are not amenable to therapeutic use. 

Growth hormone, or somatotropin, is a protein that stimulates linear body growth in children and regulates cellular metabolism in both adults and children. Growth hormone stimulates lipolysis, enhances production of free fatty acids, elevates blood glucose, and promotes... 

Mechanism of Action Afibricacid derivative that inhibits lipolysis of fat in adipose tissue decreases liver uptake of free fatty acids and reduces hepatic triglyceride production. Inhibits synthesis of VLDL carrier apolipoprotein B. Therapeutic Effect Lowers serum cholesterol and triglycerides (decreases VLDL, LDL increases HDL). Pharmacokinetics Well absorbed from the GI tract. Protein binding 99%. Metabolized in liver. Primarily excreted in urine. Not removed by hemodialysis. Half-life 1.5 hr. 

PC requires biotin for activity. Biotin is bound to the enzyme via a peptide-like linkage involving e-NH2 groups of certain lysine residues. This type of biotin complex is biocytin (see Chapter 6). Another compound necessary for PC activity is acetyl-CoA, a positive effector. PC is activated as cellular levels of acetyl-CoA increase, as when extensive lipolysis takes place. Acetyl-CoA is produced in large amounts from fatty acids via the /8-oxidation reaction (see Chapter 19). PC can also be considered an anaplerotic reaction, those reactions that replenish crucial intermediates for metabolic pathways. In this case, oxaloacetate, an important intermediate in the Krebs cycle, is replenished by a reaction catalyzed by PC. 

The role of milk-fat in the development of flavor in cheese during ripening will be discussed below although it should not be forgotten that lipolysis and the metabolism of fatty acids do not occur in isolation from other important biochemical events during ripening. 

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. 

Free fatty acids, whose levels are generally raised by insulin or alcohol, influence the rate of VLDL synthesis and hence the concentration of triglycerides. About 16 g glycerol, which are mainly utilized in the liver, are released daily by lipolysis, and about 120 g free fatty acids are made available for generating energy in the heart and skeletal musculature (75%) as well as in the liver itself (25%o). These free fatty acids are bound in the plasma to albumin (50%) and lipoproteins (50%). Their extremely short plasma half-life of approx. 2 minutes emphasizes their high metabolic activity. Fatty acids are present in the plasma in saturated (no double bond) and unsaturated (various numbers of double bonds) forms. Essential fatty acids cannot be synthesized by the body, which means they must be obtained from food intake. The most important ones are multiple unsaturated fatty acids such as linolic acid (Cis-fatty acid, 2 double bonds), linolenic acid (Ci8-fatty acid, 3 double bonds), and arachidonic acid (C2o-fatty acid, 4 double bonds). Their prime function is to act as precursors for the synthesis of eicosan-oids. (s. fig. 3.10)... 

Alcohol-induced ketoacidosis must be differentiated from a similar metabolic complication in diabetes melli-tUS (E.S. Dillon et al., 1940 D.W. Jenkins et al., 1971). With chronic alcohol consumption and concurrent malnutrition, metabolic acidosis is caused by a still unclear multifaceted pathogenesis (hypoinsulinaemia, lipolysis, extreme increase in free fatty acids, rise in ketone bodies). The clinical picture shows nausea, vomiting, dehydration, hyperventilation, fruity odour on breath, aceton-uria and acetonaemia as well as a moderate form of hyperglycaemia. This syndrome probably occurs more often than has been hitherto assumed. (54)... 

---