Regulation of carnitine palmitoyltransferase activity by malonyl-CoA in mitochondria from sheep liver, a tissue with a low capacity for fatty acid synthesis

Abstract

The characteristics of inhibition of carnitine palmitoyltransferase (CPT) I by malonyl-CoA were studied for the enzyme in mitochondria isolated from sheep liver, a tissue with a very low rate of fatty acid synthesis. Malonyl-CoA was as potent in inhibiting the sheep liver enzyme as in inhibiting the enzyme in rat liver mitochondria. CPT I in guinea-pig liver mitochondria was also similarly inhibited. The inhibition showed the same time-dependent characteristics previously established for the rat liver enzyme. Methylmalonyl-CoA was as effective an inhibitor of CPT I as malonyl-CoA in sheep liver mitochondria, but did not affect CPT I activity in mitochondria from rat or guinea-pig liver. The concentrations of malonyl-CoA required to inhibit CPT I in sheep liver mitochondria in vitro were similar to those found in freeze-clamped sheep liver samples (about 7 nmol of malonyl-CoA/g wet wt.). In sheep liver cells the content of malonyl-CoA was only one-tenth of that observed in vivo when glucose only was added to the incubation medium. Inclusion of acetate and/or insulin increased the malonyl-CoA content about 10-fold, to values similar to those observed in vivo. The rate of fatty acid synthesis in sheep liver cells was about 1% of that observed in rat liver, but was correlated with the concentrations of malonyl-CoA in the cells under various incubation conditions. These observations are discussed in relation to (i) the regulatory role of malonyl-CoA in tissues that have a low capacity for fatty acid synthesis, and (ii) the utilization by sheep liver of propionate as a gluconeogenic precursor.

Effects of Hyperinsulinaemia under Euglycaemic Condition on Liver Fat Metabolism in Dairy Cows in Early and Mid‐lactation

“…Insulin stimulates the production of malonyl–CoA in hepatocytes, which is one of the key factors in the LCFA synthesis. Malonyl‐CoA is a powerful inhibitor of LCFA oxidation in sheep liver (Brindle et al., 1985) potentially due to a depression of CPT‐I activity and thereby a deceased LCFA uptake into the mitochondria (Zammit, 1990; Beylot, 1996). The concentration of malonyl‐CoA in sheep liver is in the range of what has been reported for rat liver and changes with physiological state similar to rats (Brindle et al., 1985).…”

“…Malonyl‐CoA is a powerful inhibitor of LCFA oxidation in sheep liver (Brindle et al., 1985) potentially due to a depression of CPT‐I activity and thereby a deceased LCFA uptake into the mitochondria (Zammit, 1990; Beylot, 1996). The concentration of malonyl‐CoA in sheep liver is in the range of what has been reported for rat liver and changes with physiological state similar to rats (Brindle et al., 1985). Despite the fact that ruminant liver tissue has been evaluated to have a low rate of fatty acid synthesis (Ingle et al., 1972; Bruss, 1993), it seems possible that malonyl‐CoA in ruminant liver could serve a regulatory function, rather than serving as a quantitative source of the LCFA synthesis.…”

Role of insulin in hepatic fatty acid partitioning: emerging concepts

“…Because of the high fatty acid synthase\ACC activity ratio, and the relatively low affinity of fatty acid synthase for malonyl-CoA, the concentration of the inhibitor of CPT I is determined largely by the activity of ACC [37]. Insulin can potentially activate ACC through a variety of mechanisms (see [38]), including dephosphorylation of serine residues in the protein [39], the phosphorylation of which results in enzyme inhibition [40], direct (activatory) phosphorylation at an ' insulin site ' [41], or possibly through the action of a lowmolecular-mass effector [42].…”

Vitamin B12 Status among Pregnant Women in the UK and Its Association with Obesity and Gestational Diabetes

“…One step in this process is the conversion of homocysteine (Hcy) to a methyl donor, methionine, for which B12 and folate are necessary cofactors. Additionally, the mitochondrial conversion of methylmalonyl-CoA to succinyl-CoA requires B12 as a coenzyme and in its absence, accumulation of the former compound inhibits fatty acid oxidation, thereby promoting lipogenesis [7,8]. Therefore it can be postulated that low B12, at a cellular level, may be linked to adipocyte dysfunction and obesity-related complications by modulating lipid metabolism, cellular inflammation [9], and causing hypomethylation of cholesterol biosynthesis pathways [10].…”