Short-chain fatty acids metabolism

Clements, K.D., Gleeson, V.R, and Slaytor, M., Short-chain fatty acid metabolism in temperate marine herbivorous fish, J. Comp. Physiol. B, 164, 372, 1994. 

This first sample came from the urine of a patient suffering from a short-chain fatty acid metabolism defect (short-chain acylCoA dehydrogenase deficiency). As a comparison, the spectrum of a urine sample from a patient suffering from a medium-chain fatty acid metabolism defect (medium-chain acylCoA dehydrogenase deficiency) is displayed in Figure 4.14. Other examples of selectivity obtained by MS/MS are given in Chapter 5. 

Elsen, R.J., and Bisirian, B.R. 1991. Recent Developments in Short-Chain Fatty-Acid Metabolism. Nutr 7(1), 7-10. 

It is of interest that one of the cases of Sidbury et al (1967), who were described as having hexanoic and butanoic aciduria due to a proposed defect in short-chain fatty acid metabolism located at green acyl-CoA (butyryl-CoA) dehydrogenase, was subsequently shown to have isovaleric acidaemia (Ando et al, 1973) (Case 4, Family II of Sidbury etal, 1967). It is possible that the other three cases of Sidbury et al (1967) (Cases 1-3, Family I) also had isovaleric... 

Sidbury, J.B., Smith, E.K. and Harlan, W. (1967), An inborn error of short chain fatty acid metabolism. J. Pediatr., 70,8. 

Wegener WS, HC Reeves, R Rabin, SJ Ajl (1968) Alternate pathways of metabolism of short-chain fatty acids. Bacterial Rev 32 1-26. 

In developed conntries, fat provides about 40% of the total energy consnmed but in some individuals this percentage may be mnch higher. Almost all of this is in the form of triacylglycerol, containing mainly long-chain bnt also some short-chain fatty acids. The stractnre, digestion, absorption and eventual fate of the products of absorption are described in Chapters 4 and 5 and the metabolism of fat is discussed in Chapter 7. 

Many short chain fatty acids, aldehydes, alcohols, esters, ketones and hydrocarbons are produced by metabolism of fatty acids (Cie-Cis). These compounds are common in essential oils and are also found in insects. 

Griner RD, Aleo MD, Schnellmann RG (1993), The role of short chain fatty acid substrates in aerobic and glycolytic metabolism in primary cultures of renal proximal tubule cells, In Vitro Cell Dev. Biol. Anim. 29A 649-655. 

There are several theories behind the cause of hepatic encephalopathy. One of these is that the accumulation of toxins in the brain, particularly ammonia, is the cause. Ammonia is produced in the intestine and is usually metabolised in the liver to urea via the urea cycle. As a result of portosystemic shunting and reduced metabolism in the liver, ammonia serum levels rise as the transformation to urea is reduced. However, the validity of this theory is questionable as not all patients with signs of hepatic encephalopathy have raised serum ammonia levels. Another theory is that patients with hepatic encephalopathy have increased permeability of the blood-brain barrier, and hence the increased toxin levels permeate the brain more than usual, leading to altered neuropsychiatric function. There are also theories relating to increased levels of neurotransmitters, short-chain fatty acids, manganese and increased GABA-ergic transmission. 

With hepatic encephalopathy, there is often an increase in short-chain fatty acids such as propionate, butyrate, valerate and octa-noate in the serum and CSF. They are formed as a result of incomplete p-oxidation of long-chain fatty acids in the intestine. They are not - or only inadequately — metabolized in the damaged liver. The neuro toxic effect is based upon inhibition of various enzymes (including enzymes of the urea cycle) and competitive... 

The energy required for hepatocellular metabolism is mainly provided by oxidation of short-chain fatty acids and amino acids via the citric acid cycle, usually in the mitochondria. Fructose and ethanol are also available for oxidation. In this process, Oj partial pressure falls from 13% in the jreriportal area to 6% in the pericentral area, which means that the latter region is the most prone to hypoxic cellular damage. 

The initial step in the metabolism of short-chain fatty acids, w hether In cells of the gut lining or in the liver, is conversion to the coenzyine A derivative. For example, acetate is converted to acetyl coeuzyme A (acetyl CoA). The acetyl Co A formed in the cytoplasm can be used for the synthesis of fatly acids, w hereas that formed In the mitochondria can be used for immediate oxidation. Propioriyl CoA can be metabolized as shown in Figure8.7 in Chapter 8. Butyric acid can enter the mitochondria for conversion to butyryl CoA and oxidation in the pathway of fatty acid oxidation. 

Redox reactions and hydrolysis are the predominant metabolic conversions triggered by the intestinal microflora. The primary reductive enzymes produced by the intestinal microflora are nitroreductase, deaminase, urea dehydroxylase, and azoreductase. The hydrolytic enzymes are p-glucuronidase, p-xylosidase, p-galactosidase, and ot-L-arabinosidase. Studies conducted by Macfarlane and coworkers have shown that proteolysis can also occur in the colon. More recent findings by the group indicate that bacterial fermentation of proteins in humans could account for 17% of the short-chain fatty acids in the cecum and for 38 /o in the sigmoid and the rectum. ... 

The primary fate of dietary fibers is digestion and catabolism by the gut microflora to short-chain fatty acids and carbon dioxide. The major products of this microbial metabolism — acetic, propionic, and butyric acid — are important sources of energy for ruminants (sheep, cows). Dietary fiber is retained in a chamber of their gastrointestinal tracts, called the rumen, where it is converted to short-chain fatty acids by the gut microflora. The fatty acids produced may supply 35-75% of the energy requirement of the ruminant. 

Carnitine is required for transport of long-chain fatty adds into mitochondria hence, carnitine plays an essential role in normal oxidative metabolism as well as in the formation of ketone bodies. The concentration of free carnitine in muscle is about 4.0 mmol/kg. The concentration of carnitine boimd to long-chain fatty adds (fatty acyl-camitine) is lower, about 0.2 mmol/kg. Short-chain fatty acids, including acetic, are also esterified to carnitine, but the functions of these complexes are not clear. There is some indication that keto forms of BCAAs (BCKAs) can also be esterified to carnitine. These complexes can then be transported into the mitochondria for complete oxidation of the BCKAs. The importance of this mode of BCKA transport is not clear (Takakura et ah, 1997). 

Butanal is readily metabolized to carbon dioxide by conversion to butyryl CoA and subsequent metabolism via the pathways of short-chain fatty acid oxidation. Detoxication by reaction with glutathione also occurs. Clearance is rapid and complete. 

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