Lipid Transport and Storage Medical Biochemistry Lectures #54 and #55

CLINICAL ASPECTS: 1. Imbalance in the rate of triacylglycerol formation and export causes fatty liver. Accumulation of lipid as triacylglycerol in the liver causes cirrhosis and impaired liver function.

Fatty liver falls into two categories: a. Raised levels of plasma free fatty acids resulting from mobilization of fat from adipose tissue or from the hydrolysis of lipoprotein triacylglycerol by lipoprotein lipase in extrahepatic tissues. Increasing amounts of free fatty acids are taken up by the liver and esterified. The production of VLDL does not keep pace with the influx of free fatty acids, allowing triacylglycerol to accumulate, causing fatty liver. During starvation, quantity of triacylglycerol in the liver is increased, and ability to secret VLDL is impaired. This may be due to low levels of insulin.

b. Due to a metabolic block in the production of plasma lipoproteins, thus allowing triacylglycerol to accumulate. Lesion could be due to: 1. A block in apolipoprotein synthesis 2. A block in the synthesis of lipoprotein from lipid and apolipoprotein 3. A failure in the secretory mechanism itself. In experimental animals, deficiency of choline, treatment with puromycin, ethionine, carbon tetrachloride, chloroform, phosphorous, lead, and arsenic causes fatty liver.

Ethanol also causes fatty liver: Alcoholism leads to fat accumulation in the liver, hyperlipidemia, and ultimately cirrhosis

A. Increased NADH/NAD+ ratio causes Shift in the malate oxaloacetate, which may reduce activity of the citric acid cycle. Net effect of inhibiting fatty acid oxidation is to cause increased esterification of fatty acids in triacylglycerol, which may be the cause of fatty liver. B. also causes increase in lactate/pyruvate ratio that results in hyperlacticacidemia, which in turn decreases the capacity of kidney to excrete uric acid. C. Increase in acetyl-CoA causes increased lipogenesis and cholesterol