Liver triacylglycerol synthesis

Causes a decrease in liver triacylglycerol synthesis by limiting available free fatty acids needed as building blocks for this pathway. 

PA is the precursor of many other phosphoglycerides. The steps in its synthesis from glycerol phosphate and two fatty acyl CoAs were illustrated in Figure 16.14, p. 187, in which PA is shown as a precursor of triacylglycerol. [Note Essentially all cells except mature ery-. throcytes can synthesize phospholipids, whereas triacylglycerol synthesis occurs essentially only in liver, adipose tissue, lactating mammary glands, and intestinal mucosal cells.]... 

VLDLs are produced in the liver (Figure 18.17). They are composed predominantly of triacylglycerol, and their function is to carry this lipid from the liver to the peripheral tissues. There, the triacylglycerol is degraded by lipoprotein lipase, as discussed for chylomicrons (see p. 226). [Note "Fatty liver" (hepatic steatosis) occurs in conditions in which there is an imbalance between hepatic triacylglycerol synthesis and the secretion of VLDL. Such conditions include obesity, uncontrolled diabetes mellitus, and chronic ethanol ingestion.]... 

Table 2 Inhibition of Triacylglycerol Synthesis by DGAT Inhibitors in Assays Using Rat Liver Microsomes and Intact Raji Cells...

Fats are catabolised by hydrolysis to free fatty acids and glycerol. Tbe free fatty acid is metabolised in the liver and peripheral tissue via /S-oxidation into acetyl CoA acetyl-CoA then enters the TCA cycle. Glycerol is used by the liver for triacylglycerol synthesis or for gluconeogenesis (following its conversion to 3-phosphoglycerate). 

The liver is the primary site of triacylglycerol synthesis. From the liver, the triacylglycerols are transported to the muscles for energy conversion or to the adipocytes for storage. 

After a meal, fructose 2,6-bisphosphate is high, PFK1 is activated, and glycolysis is stimulated. The liver is using glycolysis to produce fatty acids for triacylglycerol synthesis. 

Alcoholism affects about 10% of the drinking population and alcohol (ethanol) abuse has been implicated in at least 20% of admissions to general hospitals. This chronic disease exhibits high mortality due to a wide variety of factors. Ethanol produces effects in virtually every organ system. The biochemical effects of ethanol are due to increased production of NADH that decreases the [NAD ]/[NADH] ratio in the cytoplasm of liver cells at least tenfold from the normal value of about 1000. Increased production of lactate and inhibition of gluconeo-genesis (Chapter 15) result. The hyperuricemia associated with ethanol consumption has been attributed to accelerated turnover of adenine nucleotides and their catabolism to uric acid (Chapter 27). Alcohol increases hepatic fatty acid and triacylglycerol synthesis and mobilization of fat from adipose tissue, which can lead to fatty liver, hepatitis, and cirrhosis. These effects are complicated by a deficiency of B vitamins and protein. 

However, ethanol ingestion also has acute effects on liver metabolism, including inhibition of fatty acid oxidation and stimulation of triacylglycerol synthesis, leading to a fatty liver. It also can result in ketoacidosis or lactic acidosis and cause hypoglycemia or hyperglycemia, depending on the dietary state. These effects are considered reversible. 

The glycerol released from chylomicron triacylglycerols by LPL may be used for triacylglycerol synthesis in the liver in the fed state. 

A. Mechanisms That Affect Glycogen and Triacylglycerol Synthesis in Liver... 

Table 36.3. Regulation of Liver Enzymes Involved in Glycogen, Blood Glucose, and Triacylglycerol Synthesis and Degradation ...

Growth hormone increases the sensitivity of the adipocyte to the lipolytic action of the catecholamines and decreases its sensitivity to the lipogenic action of insulin. These actions lead to the release of free fatty acids and glycerol into the blood to be metabolized by the liver. GH also decreases esterification of fatty acids, thereby reducing triacylglycerol synthesis within the fat cell. Recent evidence suggests that GH may impair glucose uptake by both fat and muscle cells by a postreceptor inhibition of insulin action. 

Muoio, D.M. Seefeld, K. Witters, L.A. Coleman, R.A. AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle evidence that sn-glycerol-3-phosphate acyltransferase is a novel target. Biochem. J., 338, 783-791 (1999)... 

Figure 11.10 Interactions between fatty acid synthesis and oxidation in liver. In the fed state malonyl-CoA levels are high. This allows rapid fatty acid synthesis and inhibits jS-oxidation by lowering carnitine acyltransferase I activity. If triacylglycerol synthesis is impaired then acyl-CoAs will feedback to inhibit acetyl-CoA carboxylase. In the fed state this does not normally happen and tri-acylglycerols are incorporated into very-low-density lipoprotein for export to extrahepatic tissues. Glucagon excess in fasting leads to a suppression of glycolysis, cessation of lipogenesis and activation of -oxidation and ketogenesis. Reproduced with permission from Annual Review of Biochemistry, 49, 1980 by Annual Reviews Inc.

Reduce hepatic fatty acid synthetase, triacylglycerol synthesis in liver, VLDL triacylglycerol production, ApoB synthesis Increase tissue deposition of cholesterol, HDL cholesterol... 

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