Harpers

212 / CHAPTER 25the fed state rather than the starved state; (2) the feedingof diets high in carbohydrate (particularly if theycontain sucrose or fructose), leading to high rates of lipogenesisand esterification of fatty acids; (3) high levelsof circulating free fatty acids; (4) ingestion ofethanol; and (5) the presence of high concentrations ofinsulin and low concentrations of glucagon, which enhancefatty acid synthesis and esterification and inhibittheir oxidation (Figure 25–6).CLINICAL ASPECTSImbalance in the Rate of TriacylglycerolFormation & Export Causes Fatty LiverFor a variety of reasons, lipid—mainly as triacylglycerol—canaccumulate in the liver (Figure 25–6). Extensiveaccumulation is regarded as a pathologic condition.When accumulation of lipid in the liver becomeschronic, fibrotic changes occur in the cells that progressto cirrhosis and impaired liver function.Fatty livers fall into two main categories. The firsttype is associated with raised levels of plasma freefatty acids resulting from mobilization of fat from adiposetissue or from the hydrolysis of lipoprotein triacylglycerolby lipoprotein lipase in extrahepatic tissues.The production of VLDL does not keep pace with theincreasing influx and esterification of free fatty acids, allowingtriacylglycerol to accumulate, causing a fattyliver. This occurs during starvation and the feeding ofhigh-fat diets. The ability to secrete VLDL may also beimpaired (eg, in starvation). In uncontrolled diabetesmellitus, twin lamb disease, and ketosis in cattle,fatty infiltration is sufficiently severe to cause visiblepallor (fatty appearance) and enlargement of the liverwith possible liver dysfunction.The second type of fatty liver is usually due to ametabolic block in the production of plasma lipoproteins,thus allowing triacylglycerol to accumulate.Theoretically, the lesion may be due to (1) a block inapolipoprotein synthesis, (2) a block in the synthesis ofthe lipoprotein from lipid and apolipoprotein, (3) afailure in provision of phospholipids that are found inlipoproteins, or (4) a failure in the secretory mechanismitself.One type of fatty liver that has been studied extensivelyin rats is due to a deficiency of choline, whichhas therefore been called a lipotropic factor. The antibioticpuromycin, ethionine (α-amino-γ-mercaptobutyricacid), carbon tetrachloride, chloroform, phosphorus,lead, and arsenic all cause fatty liver and a markedreduction in concentration of VLDL in rats. Cholinewill not protect the organism against these agents butappears to aid in recovery. The action of carbon tetrachlorideprobably involves formation of free radicalscausing lipid peroxidation. Some protection against thisis provided by the antioxidant action of vitamin E-supplementeddiets. The action of ethionine is thought tobe due to a reduction in availability of ATP due to itsreplacing methionine in S-adenosylmethionine, trappingavailable adenine and preventing synthesis ofATP. Orotic acid also causes fatty liver; it is believed tointerfere with glycosylation of the lipoprotein, thus inhibitingrelease, and may also impair the recruitment oftriacylglycerol to the particles. A deficiency of vitaminE enhances the hepatic necrosis of the choline deficiencytype of fatty liver. Added vitamin E or a sourceof selenium has a protective effect by combating lipidperoxidation. In addition to protein deficiency, essentialfatty acid and vitamin deficiencies (eg, linoleic acid,pyridoxine, and pantothenic acid) can cause fatty infiltrationof the liver.Ethanol Also Causes Fatty LiverAlcoholism leads to fat accumulation in the liver, hyperlipidemia,and ultimately cirrhosis. The exactmechanism of action of ethanol in the long term is stilluncertain. Ethanol consumption over a long periodleads to the accumulation of fatty acids in the liver thatare derived from endogenous synthesis rather than fromincreased mobilization from adipose tissue. There is noimpairment of hepatic synthesis of protein after ethanolingestion. Oxidation of ethanol by alcohol dehydrogenaseleads to excess production of NADH.CH 3 CH 2 OHEthanolALCOHOLDEHYDROGENASENAD + NADH + H +CH 3CHOAcetaldehydeThe NADH generated competes with reducingequivalents from other substrates, including fatty acids,for the respiratory chain, inhibiting their oxidation, anddecreasing activity of the citric acid cycle. The net effectof inhibiting fatty acid oxidation is to cause increasedesterification of fatty acids in triacylglycerol, resultingin the fatty liver. Oxidation of ethanol leads to the formationof acetaldehyde, which is oxidized by aldehydedehydrogenase, producing acetate. Other effects ofethanol may include increased lipogenesis and cholesterolsynthesis from acetyl-CoA, and lipid peroxidation.The increased [NADH]/[NAD + ] ratio also causes increased[lactate]/[pyruvate], resulting in hyperlacticacidemia,which decreases excretion of uric acid, aggravatinggout. Some metabolism of ethanol takes placevia a cytochrome P450-dependent microsomal ethanoloxidizing system (MEOS) involving NADPH and O 2 .This system increases in activity in chronic alcoholism