Extra-hepatic tissues

When ketone bodies are being metabolized in extra-hepatic tissues there is an alternative reaction catalyzed by succinyl-CoA-acetoacetate-CoA transferase (thio-phorase)—involving transfer of CoA from succinyl-CoA to acetoacetate, forming acetoacetyl-CoA (Chapter 22). 

Insulin is secreted as a direct response to hyperglycemia it stimulates the liver to store glucose as glycogen and facilitates uptake of glucose into extra-hepatic tissues. 

Fig. 9-4). Very low-density lipoprotein particles are released into the circulation where they acquire apolipoprotein E and apolipoprotein C-II from HDL. Very-low density lipoprotein loses its triglyceride content through the interaction with LPL to form VLDL remnant and IDL. Intermediate-density lipoprotein can be cleared from the circulation by hepatic LDL receptors or further converted to LDL (by further depletion of triglycerides) through the action of hepatic lipases (HL). Approximately 50% of IDL is converted to LDL. Low-density lipoprotein particles are cleared from the circulation primarily by hepatic LDL receptors by interaction with apolipoprotein B-100. They can also be taken up by extra-hepatic tissues or enter the arterial wall, contributing to atherogenesis.4,6... 

In the body retinol can also be made from the vitamin precursor carotene. Vegetables like carrots, broccoli, spinach and sweet potatoes are rich sources of carotene. Conversion to retinol can take place in the intestine after which retinyl esters are formed by esterifying retinol to long chain fats. These are then absorbed into chylomicrons. Some of the absorbed vitamin A is transported by chylomicrons to extra-hepatic tissues but most goes to the liver where the vitamin is stored as retinyl palmitate in stellate cells. Vitamin A is released from the liver coupled to the retinol-binding protein in plasma. 

Succinyl coenzyme A 3-oxo acid transferase catalyses the transformation of ACAC into acetoacetyl coenzyme A in the mitochondria of extra-hepatic tissues. This enzyme defect may be suggested in cases of severe ketoacidosis often associated with neurologic dysfunction [16]. 

Transport of retinol from the liver to extra-hepatic tissues occurs by binding of hydrolyzed retinol to retinol binding protein (RBP). 

Within extra hepatic tissues retinol is bound to cellular retinol binding protein (CRBP). 

The major sites of cholesterol synthesis are the liver and the intestines. Generally, about 1/3 of our cholesterol arises from the diet, while 2/3 is made in the body (Jones, 1997), Most of the cholesterol in the body is manufactured by extra-hepatic tissues. This statement applies to most animals, except for rats and mice, where the liver makes most of the body s cholesterol (Dietschy, 1997). Nearly all the cholesterol synthesized in the liver is used for bile salt synthesis. The high contribution of the intestines to the body s synthesis of cholesterol is due to their large surface area and rapid turnover, as discussed in the section on the crypt and villus in Chapter 2,... 

HDLs are the smallest of the lipoproteins. The HDL particle is S3mthesized mainly by the liver, and also by the intestines. When excess cholesterol occurs in extra-hepatic tissues, it is picked up by HDLs by a process called reverse cholesterol transport. Apo A-I is the vital and defining protein of the HDL. Each HDL particle contains 2-4 molecules of Apo A-I. When secreted by the liver, HDLs are lipid-poor... 

Acetoacetate and 6-hydroxybutyrate are products of normal metabolism of fatty acid oxidation and serve as metabolic fuels in extrahepatic tissues. Their level in blood depends on the rates of production and utilization. Oxidation increases as their plasma level increases. Some extra-hepatic tissues (e.g., muscle) oxidize them in preference to glucose and fatty acid. Normally, the serum concentration of ketone bodies is less than 0.3 mM/L. 

Action of endolhalfal fipoprotem fipose In adipose, muscle, and 01 her extra hepatic tissues (progressive dehpidalion)... 

IDO is a key enzyme in the degradation of tryptophan in extra-hepatic tissues [37], through the generation of AAformyl kynurenine which is further degraded to kynurenine (l-KYN) by formamidase. In addition to its potential role in neurodegeneration, inhibition of IDO has been implicated as an important new therapeutic target for the treatment of cancer through tumor immunosuppression [3, 38]. 

P450 3A4 is also expressed in some extra-hepatic tissues, including lung " stomach, colon, and adrenal (weak) . P450 3A4 does not appear to be expressed in kidney, prostate, testis, or thymus, but other 3A subfamily P450s are . The literature is mixed on whether expression occurs in peripheral blood lymphocytes or not . 

Bulera SJ, Cohen SD, Khairallah EA (1996) Acetaminophen-arylated proteins are detected in hepatic subcellular fractions and numerous extra-hepatic tissues in CD-I and C57B1/6J mice. Toxicology 109 85-99... 

A large fraction of the ammonia that is converted to urea in the liver comes from metabolism in the extra-hepatic tissues, although only a small fraction leaves these tissues as anunonia. The absorptive cells of the small intestine are exceptional in this respect, in that they release anunonia into the portal vein there the anunonia concentration may reach 0.26 mM, accoiuiting for 30% of the urea synthesized in the liver. 

Lipoprotein 0-carotene Extra hepatic tissue 0-carotene 0.70 0.092 0.835... 

PPAR Could Mediate Fatty Acid Regulation of Lipid-Metabolism Related Genes in Hepatic and Extra-Hepatic Tissues... 

The liver is clearly well equipped to utilize free fatty acids and to interconvert acetoacetate and hydroxybutyrate, but the virtual absence of 3-Oxoacid-CoA transferase and lipoprotein lipase means that any significant uptake of ketone bodies and triglycerides is restricted to extra-hepatic tissues. Heart and kidney contain the necessary enzymes to deal with all four fuels and this may reflect their high metabolic activity. Page and Williamson (1971) have shown that normal human brain has the capacity to utilize ketone bodies. 

Concerning the tissular origin of fetal arachidonic acid, the question whether the mother or fetus liver or an extra-hepatic tissue is involved, is under investigation. 

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