Clinical Aspects

Imbalance in the Rate of Triacylglycerol Formation & Export Causes Fatty Liver

For a variety of reasons, lipid—mainly as triacylglyc-erol—can accumulate in the liver (Figure 25-6). Extensive accumulation is regarded as a pathologic condition. When accumulation of lipid in the liver becomes chronic, fibrotic changes occur in the cells that progress to cirrhosis and impaired liver function.

Fatty livers fall into two main categories. The first type is associated with raised levels of plasma free fatty acids resulting from mobilization of fat from adipose tissue or from the hydrolysis of lipoprotein triacyl-glycerol by lipoprotein lipase in extrahepatic tissues. The production of VLDL does not keep pace with the increasing influx and esterification of free fatty acids, allowing triacylglycerol to accumulate, causing a fatty liver. This occurs during starvation and the feeding of high-fat diets. The ability to secrete VLDL may also be impaired (eg, in starvation). In uncontrolled diabetes mellitus, twin lamb disease, and ketosis in cattle, fatty infiltration is sufficiently severe to cause visible pallor (fatty appearance) and enlargement of the liver with possible liver dysfunction.

The second type of fatty liver is usually due to a metabolic block in the production of plasma lipo-proteins, thus allowing triacylglycerol to accumulate. Theoretically, the lesion may be due to (1) a block in apolipoprotein synthesis, (2) a block in the synthesis of the lipoprotein from lipid and apolipoprotein, (3) a failure in provision of phospholipids that are found in lipoproteins, or (4) a failure in the secretory mechanism itself.

One type of fatty liver that has been studied extensively in rats is due to a deficiency of choline, which has therefore been called a lipotropic factor. The antibiotic puromycin, ethionine (a-amino-y-mercaptobu-tyric acid), carbon tetrachloride, chloroform, phosphorus, lead, and arsenic all cause fatty liver and a marked reduction in concentration of VLDL in rats. Choline will not protect the organism against these agents but appears to aid in recovery. The action of carbon tetrachloride probably involves formation of free radicals causing lipid peroxidation. Some protection against this is provided by the antioxidant action of vitamin E-sup-plemented diets. The action of ethionine is thought to be due to a reduction in availability of ATP due to its replacing methionine in S-adenosylmethionine, trapping available adenine and preventing synthesis of ATP. Orotic acid also causes fatty liver; it is believed to interfere with glycosylation of the lipoprotein, thus inhibiting release, and may also impair the recruitment of triacylglycerol to the particles. A deficiency of vitamin E enhances the hepatic necrosis of the choline deficiency type of fatty liver. Added vitamin E or a source of selenium has a protective effect by combating lipid peroxidation. In addition to protein deficiency, essential fatty acid and vitamin deficiencies (eg, linoleic acid, pyridoxine, and pantothenic acid) can cause fatty infiltration of the liver.

Ethanol Also Causes Fatty Liver

Alcoholism leads to fat accumulation in the liver, hy-perlipidemia, and ultimately cirrhosis. The exact mechanism of action of ethanol in the long term is still uncertain. Ethanol consumption over a long period leads to the accumulation of fatty acids in the liver that are derived from endogenous synthesis rather than from increased mobilization from adipose tissue. There is no impairment of hepatic synthesis of protein after ethanol ingestion. Oxidation of ethanol by alcohol dehydrogenase leads to excess production of NADH.

alcohol dehydrogenase

NAD+ NADH + H+ Ethanol Acetaldehyde

The NADH generated competes with reducing equivalents from other substrates, including fatty acids, for the respiratory chain, inhibiting their oxidation, and decreasing activity of the citric acid cycle. The net effect of inhibiting fatty acid oxidation is to cause increased esterification of fatty acids in triacylglycerol, resulting in the fatty liver. Oxidation of ethanol leads to the formation of acetaldehyde, which is oxidized by aldehyde dehydrogenase, producing acetate. Other effects of ethanol may include increased lipogenesis and cholesterol synthesis from acetyl-CoA, and lipid peroxidation. The increased [NADH]/[NAD+] ratio also causes increased [lactate]/[pyruvate], resulting in hyperlactic-acidemia, which decreases excretion of uric acid, aggravating gout. Some metabolism of ethanol takes place via a cytochrome P450-dependent microsomal ethanol oxidizing system (MEOS) involving NADPH and O2. This system increases in activity in chronic alcoholism

VLDL

BLOOD

Nascent VLDL

Apo C Apo E

BLOOD

Nascent VLDL

Apo C Apo E

Apolipoprotein Synthesis

Figure 25-6. The synthesis of very low density lipoprotein (VLDL) in the liver and the possible loci of action of factors causing accumulation of triacylglycerol and a fatty liver. (EFA, essential fatty acids; FFA, free fatty acids; HDL, high-density lipoproteins; Apo, apolipoprotein; M, microsomal triacylglycerol transfer protein.) The pathways indicated form a basis for events depicted in Figure 25-2. The main ¡triacylglycerol | pool in liver is not on the direct pathway of VLDL synthesis from acyl-CoA. Thus, FFA, insulin, and glucagon have immediate effects on VLDL secretion as their effects impinge directly on the small triacylglycerol* precursor pool. In the fully fed state, apo B-100 is synthesized in excess of requirements for VLDL secretion and the surplus is destroyed in the liver. During translation of apo B-100, microsomal transfer protein-mediated lipid transport enables lipid to become associated with the nascent polypeptide chain. After release from the ribosomes, these particles fuse with more lipids from the smooth endoplasmic reticulum, producing nascent VLDL.

Figure 25-6. The synthesis of very low density lipoprotein (VLDL) in the liver and the possible loci of action of factors causing accumulation of triacylglycerol and a fatty liver. (EFA, essential fatty acids; FFA, free fatty acids; HDL, high-density lipoproteins; Apo, apolipoprotein; M, microsomal triacylglycerol transfer protein.) The pathways indicated form a basis for events depicted in Figure 25-2. The main ¡triacylglycerol | pool in liver is not on the direct pathway of VLDL synthesis from acyl-CoA. Thus, FFA, insulin, and glucagon have immediate effects on VLDL secretion as their effects impinge directly on the small triacylglycerol* precursor pool. In the fully fed state, apo B-100 is synthesized in excess of requirements for VLDL secretion and the surplus is destroyed in the liver. During translation of apo B-100, microsomal transfer protein-mediated lipid transport enables lipid to become associated with the nascent polypeptide chain. After release from the ribosomes, these particles fuse with more lipids from the smooth endoplasmic reticulum, producing nascent VLDL.

and may account for the increased metabolic clearance in this condition. Ethanol will also inhibit the metabolism of some drugs, eg, barbiturates, by competing for cytochrome P450-dependent enzymes.

Ethanol

In some Asian populations and Native Americans, alcohol consumption results in increased adverse reactions to acetaldehyde owing to a genetic defect of mito-chondrial aldehyde dehydrogenase.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

Get My Free Ebook


Post a comment