Regulation of Fatty Acid Oxidation

Sherratt, H. S., 1994. Introduction The regulation of fatty acid oxidation in cells. Biochemical Society Transactions 22 421—422. 

Lopa.schnk, G. D., and Gamble, J., 1994. The 1993 Merck Fro.s.st Award. Acetyl-CoA carboxylase an important regulator of fatty acid oxidation in die heart. Canadian Journal of Physiology and Pharmacology 72 1101 — 1109. 

Guzman, M. Geelen, M.J.H. (1993). Review. Regulation of fatty acid oxidation in mammalian liver. Biochim. Biophys. Acta 1167, 227-241. 

The activity of carnitine palmitoyltransferase-I plays an important role in the regulation of fatty acid oxidation malonyl-CoA is an allosteric exhibitor of the enzyme. Malonyl-CoA is a key intermediate in fatty acid synthesis, which ensures that fatty acid oxidation is decreased when synthesis is taking place. Nonetheless, malonyl-CoA has a major role in the control of fatty acid oxidation in all tissues in which fatty acid oxidation occurs, even if no synthesis takes place. 

Malonyl-CoA is also involved in the regulation of fatty acid oxidation, via inhibition of carnitine palmitoyltransferase. In non-lipogenic tissues, the only role of the carboxylase is provision of malonyl-CoA for regulation of the rate of fatty acid oxidation. 

We now take a closer look at the first stage of fatty acid oxidation, beginning with the simple case of a saturated fatty acyl chain with an even number of carbons, then turning to the slightly more complicated cases of unsaturated and odd-number chains. We also consider the regulation of fatty acid oxidation, the j8-oxidative processes as they occur in organelles other than mitochondria, and, finally, two less-general modes of fatty acid catabolism, a oxidation and [Pg.637]

Although it has been known for several years that leptin can activate AMPK, recently this pathway has come into focus as it was demonstrated to be of utmost importance in regulating food intake in the hypothalamus (Minokoshi et al. 2002, 2004). AMPK plays a particularly important role in the regulation of fatty acid oxidation. Fatty acids which are not oxidized are stored in cytoplasm as triglycerides. Malonyl CoA is an important fatty acid in maintaining a balance between storage of fatty acids and transport into the mitochondria for oxidation. Elevated malonyl CoA results in impaired transport into the mitochondria and consequently... 

B. B. Rasmussen and R.R. Wolfe. 1999. Regulation of fatty acid oxidation in skeletal mv c Q Annu. Rev. Nutr. 19 463-484. (PubMed)... 

The regulation of fatty acid oxidation, fatty acid synthesis and ketone body synthesis in the liver is summarized in fig. 10.10 ... 

FIGURE 4.47 Regulation of fatty acid oxidation by malonyl-CoA. Carboxylase catalyzes the first step of fatty acid synthesis (ttl). An increase in its activity results in an increase in the levels of malonyl-CoA in the cell (X2). Increased levels of malonyl-CoA inhibit the transport of fatty acids intn the mitnehondria f 3), which limits or controls their oxidation. The fatty acid oxidation pathway involves the degradation to units of acetyl-CoA ( 4), followed by conversion to COj in the Krebs cycle (S5). 

Regulation of fatty acid oxidation in cardiac muscle. 

Fig. 5. Proposed regulation of fatty acid oxidation in liver. Stimulation inhibition enzymes subject to regulation. Abbreviations ACC, acetyl-CoA carboxylase CPT, carnitine palmitoyltransferase PK, protein kinase.

In addition to the provision of fatty acids for triacylglycerol synthesis, the low but regulated rates of lipogenesis may be critical for overall control of fatty acid metabolism in humans. As discussed above, malonyl-CoA, which is the product of the ACC reaction and the only free intermediate of fatty acid synthesis, inhibits CPT-1 activity, and thereby prevents transport of fatty acids into mitochondria. Thus, the dual role of malonyl-CoA as an intermediate of fatty acid synthesis and as a regulator of fatty acid oxidation, prevents the operation of the futile cycle, in tissues where both fatty acid synthesis and oxidation can be active. 

Hopkins, T.A. Dyck, J.R.B. Lopaschuk, G.D. AMP-activated protein kinase regulation of fatty acid oxidation in the ischaemic heart. Biochem. Soc. Trans., 31, 207-212 (2003)... 

Kashfi, K., Mynatt, R.L. Cook, G.A (1994) Hepatic Carnitine Palmitoyltransferase-I Has Two Independent Inhibitory Binding Sites for Regulation of Fatty Acid Oxidation. Biochem. Biophys. Acta 1212, 245-252. 

Sulfur-substituted fatty acids, especially the 3-thia fatty acids (TTA, CH3-(CH2>i3-S-CH2-COOH), that profoundly affect P-oxidation, have facilitated studies on the concerted regulation of fatty acid oxidation and TG-biosynthesis. We have demonstrated that stimulation of p-oxidation (Table 2) may affect both TG-formation (Table 1) and plasma lipoprotein homeostasis (Table 1) under both normolipidemic and hyperlipidemic conditions. 

In contrast to CPT-I, the mRNA levels of CPT-II were increased in the long-term as well as in short-term experiments (Fig. 2). These results surest that the regulation of fatty acid oxidation appears to be shifted to steps(s) beyond CPT-I and CPT-II may be an important locus in the regulation of hepatic fatty acid oxidation. The proposed sequence of oxidation of fatty acids involving peroxisomal and mitochondrial P-oxidation under peroxisomal and mitochondrial proliferation is depicted in Fig. 3. A possible explanation would be that fatty acids are partially oxidized in the peroxisomes and enter the mitochondria as medimn chain fatty acids via peroxisomal CPT, like the phy-... 

Skorve, J, Asiedu, D., Rustan, A.C., Drevon, C.A., Al-Shurbaji, A., Berge, R.K. 1990. J. Lipid Res. 31 1627-1635. Regulation of fatty acid oxidation and triglyceride and phospholipid metabolism by hypolipidemic sulfiir-substituted fatty acid analogues. 

Evidence so far indicates that substrate and cofactor availability, and product inhibition, constitute the main modes for the regulation of fatty acid oxidation within mitochondria there is nothing to indicate that substrate flow over the p-oxidation spiral is further regulated by allosteric or covalent modification of the activity of any enzyme of this spiral. As is to be expected for a multistep metabolic pathway, diverse steps contribute to the overall regulation of fatty acid oxidation in different tissues under different conditions. /S/lore is known about this process in liver and heart than in other tissues and its brief description follows. 

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