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acids bound to albumin.
Within the liver, they bind to fatty acid binding proteins and are then activated
on the outer mitochondrial membrane, the peroxisomal membrane, and the smooth
endoplasmic reticulum by fatty acyl CoA synthetases. The fatty acyl group is trans-
ferred from CoA to carnitine for transport through the inner mitochondrial mem-
brane, where it is reconverted back into fatty acyl CoA and oxidized to acetyl CoA
in the -oxidation spiral (see Chapter 23).
The enzymes in the pathways of fatty acid activation and -oxidation (the syn-
thetases, the carnitine acyltransferases, and the dehydrogenases of -oxidation) are
somewhat specific for the length of the fatty acid carbon chain. The chain length
specificity is divided into enzymes for long-chain fatty acids (C20 to approximately
C12), medium-chain (approximately C12 to C4), and short-chain (C4 C2). The
major lipids oxidized in the liver as fuels are the long-chain fatty acids (palmitic,
stearic, and oleic acids), because these are the lipids that are synthesized in the liver,
are the major lipids ingested from meat or dairy sources, and are the major form of
fatty acids present in adipose tissue triacylglycerols. The liver, as well as many other
tissues, uses fatty acids as fuels when the concentration of the fatty acid albumin
complex is increased in the blood.
1. MEDIUM-CHAIN LENGTH FATTY ACID OXIDATION
The liver and certain cells in the kidney are the major sites for the oxidation of
medium-chain-length fatty acids. These fatty acids usually enter the diet of infants
CHAPTER 46 / LIVER METABOLISM 855
Medium-chain triglycerides (MCT)
in maternal milk as medium-chain-length triacylglycerols (MCT). In the intestine,
are important components of nutri-
the MCT are hydrolyzed by gastric lipase, bile salt dependent lipases, and pancre-
tional supplements used in patients
atic lipase more readily than long-chain triacylglycerols. Within the enterocytes,
with digestive disorders. They therefore can
they are neither reconverted to triacylglycerols nor incorporated into chylomicrons.
be employed as an easily absorbed source of
Instead, they are directly released into the portal circulation (fatty acids of approx-
calories in patients who have a gastrointesti-
imately 8-carbon chain lengths or less are water-soluble). In the liver, they diffuse
nal (GI) disorder that may result in malab-
through the inner mitochondrial membrane and are activated to acyl CoA deriva-
sorption of nutrients. These diseases include
tives by medium-chain-length fatty acid activating enzyme (MMFAE), a family of
pancreatic insufficiency, intraluminal bile salt
similar isozymes present only in liver and kidney. The medium-chain fatty acyl-
deficiency due to cholestatic liver disease,
CoA is then oxidized by the normal route, beginning with medium-chain-length
biliary obstruction, ileal disease or resection,
acyl CoA dehydrogenase (MCAD; see Chapter 23). and disease causing obstruction of intestinal
lymphatics. Remember, however, that MCT
do not contain polyunsaturated fatty acids
2. PEROXISOMAL OXIDATION OF VERY-LONG-CHAIN FATTY ACIDS
that can be used for synthesis of eicosanoids
Peroxisomes are present in greater number in the liver than in other tissues. Liver
(see Chapter 35).
peroxisomes contain the enzymes for the oxidation of very-long-chain fatty acids
such as C24:0 and phytanic acid, for the cleavage of the cholesterol side chain nec-
essary for the synthesis of bile salts, for a step in the biosynthesis of ether lipids,
and for several steps in arachidonic acid metabolism. Peroxisomes also contain
catalase and are capable of detoxifying hydrogen peroxide.
Very-long-chain fatty acids of C20 to C26 or greater are activated to CoA deriv-
atives by very-long-chain acyl CoA synthetase present in the peroxisomal mem-
brane. The very-long-chain acyl CoA derivatives are then oxidized in liver peroxi-
somes to the 8-carbon octanoyl CoA level. In contrast to mitochondrial -oxidation,
the first enzyme in peroxisomal -oxidation introduces a double bond and gener-
ates hydrogen peroxide instead of FAD(2H). The remainder of the cycle, however,
remains the same, releasing NADH and acetyl CoA. Peroxisomal catalase inacti-
vates the hydrogen peroxide, and the acetyl CoA can be used in biosynthetic path-
ways such as those of cholesterol and dolichol synthesis. [ Pobierz całość w formacie PDF ]

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