triacylglycerol metabolism

Medical Biochemistry

1. TAG METABOLISM & ITS FATE IN LIVER AND ADIPOSE TISSUE & FATTY LIVER Dr. M.ANUSWARU Second year Post graduate

2. DEFINITION Triacylglycerol synthesis (lipogenesis) is the synthesis of triacylglycerol through acylation of glycerol. TISSUES AND SITE Tissues active in triacylglycerol synthesis are adipose tissue, liver and small intestine. Site - Triacylglycerol synthesis occurs in the cytosol and microsomes. PATHWAYS There are three separate pathways for the synthesis of triacylglycerol. Dihydroxyacetone phosphate pathway occurring in adipose tissue and liver. Glycerol pathway occurring in the liver. 2-Monoacylglycerol pathway occurring in the small

3. Dihydroxy Acetone Phosphate Pathway Source of fatty acids Fatty acids for triacylglycerol synthesis in adipose tissue are mainly derived from hydrolysis of triacylglycerol present in chylomicrons and very low density lipoproteins (occurring in plasma) and de novo synthesis of fatty acids (in adipose tissue)from acetyl CoA that is derived from glucose. Reactions of triacylglycerol synthesis are: Formation of fatty acyl CoA - Fatty acyl CoA (activated fatty acid) is formed from fatty acids and coenzyme A in a reaction catalyzed by acyl CoA synthetase.

4. Formation of glycerol phosphate - Dihydroxyacetone phosphate is reduced to glycerol phosphate and the reaction is catalyzed by glycerol phosphate dehydrogenase. Formation of 1-acyl glycerol 3-phosphate : The first hydroxyl group of glycerol 3 phosphate is acylated to form 1 acyl glycerol 3-phosphate. The reaction is catalyzed by glycerol 3 phosphate acyl transferase. Formation of 1,2,-diacyl glycerol-3-phosphate (phosphatidic acid) -1,2,-diacylglycerol-3-phosphate is formed by acylation of 2nd hydroxyl group of 1-acyl glycerol 3-phosphate. The reaction is catalyzed by monoacyl glycerol 3-phosphate acyl transferase.

5. Formation of 1,2, -diacylglycerol : The phosphate group on C-3 of 1,2-diacylglycerol 3-phosphate is cleaved to form 1,2-diacylglycerol. The reaction is catalyzed by phosphatidic acid phosphatase. Formation of triacyl glycerol : The 3rd hydroxyl group of 1,2, diacylglycerol is acylated to form triacylglycerol. The reaction is catalyzed by the enzyme, diacylglycerol acyltransferase.

6. Glycerol Pathway Glycerol pathway occurs mainly in the liver. This pathway is similar to dihydroxyacetone pathway except for the formation of glycerol 3-phosphate from glycerol. Source of glycerol - Glycerol is derived mainly from adipose tissue lipolysis or breakdown of triacyl glycerol present in chylomicrons and VLDL. Formation of glycerol-3-phosphate - Glycerol is phosporylated to form glycerol 3-phosphate. The reaction is catalyzed by the enzyme, glycerol kinase. 2-Monoacylglycerol Pathway This pathway mainly occurs in the small intestine. Source of 2-monoacylglycerol - 2-monoacylglycerol is derived from hydrolysis of dietary triacylglycerol by the action of pancreatic lipase. Fatty acids and 2-monoacylglycerol are taken up by the mucosal cell, followed by resynthesis of triacylglycerol. Responsible for resynthesis of TAG after a meal.

7. REGULATION High carbohydrate diet, Insulin Increased availability of substrates Stimulation of glycolysis Stimulation of pentose phosphate pathway Stimulation of fatty acid synthesis Stimulation of lipogenesis

8. METABOLISM OF ADIPOSE TISSUE The adipose tissue serves as a storage site for excess calories ingested. It is made up of spherical cells, with very few mitochondria. The triglycerides form the major component of white adipose tissue (about 80%) with oleic acid being the most abundant fatty acid (50%). Brown adipose tissue is involved in thermogenesis. The brown color is due to the presence of numerous mitochondria. It is primarily important in new born human beings and adult hibernating animals. Thermogenesis is a process found in brown adipose tissue. Energy is released as heat, instead of trapping it in the high energy bonds of ATP by the action of the uncoupling protein, thermogenin . The triglycerides stored in the adipose tissue are not inert. They undergo a daily turnover with new triacylglycerol molecules being synthesized and a definite fraction being broken down. Life span of stored TAG is 2-3 days.

9. Adipose Tissue in Well-fed Condition i . Under well-fed conditions, active lipogenesis occurs in the adipose tissue. ii. The dietary triglycerides transported by chylomicrons and the endogenously synthesized triglycerides from liver brought by VLDL are both taken up by adipose tissue and esterified and stored as TAG. The lipoprotein molecules are broken down by the lipoprotein lipase present on the capillary wall. iii. In well fed condition, glucose and insulin levels are increased. GluT4 in adipose tissue is insulin dependent. Insulin increases the activity of key glycolytic enzymes as well as pyruvate dehydrogenase, acetyl CoA carboxylase and glycerol phosphate acyl transferase . The stimulant effect of insulin on the uptake of glucose by adipose tissue, on the glycolysis and on the utilization of glucose by HMP pathway also enhances lipogenesis. iv. Insulin also causes inhibition of hormone sensitive lipase, and so lipolysis is decreased

10. Adipose Tissue in Fasting Condition i . The metabolic pattern totally changes under conditions of fasting. TAG from the adipose tissue is mobilized under the effect of the hormones, glucagon and epinephrine . ii. The cyclic AMP mediated activation cascade enhances the intracellular hormone sensitive lipase . The phosphorylated form of the enzyme is active, which acts on TAG and liberates fatty acids. iii. Under conditions of starvation, a high glucagon, ACTH, glucocorticoids and thyroxine have lipolytic effect. The released free fatty acids (FFA) are taken up by peripheral tissues as a fuel.

11. Adipose Tissue and Diabetes Mellitus Lipolysis is enhanced and high FFA level in plasma is noticed in diabetes mellitus. Insulin acts through receptors on the cell surface of adipocytes. These receptors are decreased, leading to insulin insensitivity in diabetes. In type 2 diabetes mellitus, there is insulin resistance and the different insulin signaling pathways are affected differently. Hepatic gluconeogenesis occurs uninhibited leading to hyperglycemia. Increased mobilization of fatty acids from adipose tissue and the persistently high free fatty acid levels in the presence of hyperinsulinemia stimulates synthesis of triacylglycerol. The overproduction of TAG leads to increased release of VLDL from liver causing hypertriglyceridemia. The excess deposition of TAG in adipose tissue accounts for the obesity prevalent in type 2 diabetes patients.

12. FATTY LIVER Fatty liver refers to the deposition of excess triglycerides in the liver cells. The balance between the factors causing fat deposition in liver versus factors causing removal of fat from liver, determines the outcome. Causes of Fatty Liver A. Causes of fat deposition in liver 1. Mobilization of NEFA from adipose tissue. 2. More synthesis of fatty acid from glucose. B. Reduced removal of fat from liver 3. Toxic injury to liver. Secretion of VLDL needs synthesis of apo B-100 and apo C. 4. Decreased oxidation of fat by hepatic cells.

13. Alcohol ingestion results in the metabolism of alcohol to acetaldehyde by alcohol dehydrogenase and NAD is reduced to NADH + H during the reaction. Excess NADH suppresses citric acid cycle and NADH is used to generate ATP through electron transport and oxidative phosphorylation. Thus, excess citrate in the citric acid cycle is used for fatty acid synthesis and triacylglycerol synthesis.

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