Acyl-Coenzyme A Binding Protein Expression Alters Liver Fatty Acyl-Coenzyme A Metabolism

Abstract

Although studies in vitro and in yeast suggest that acyl-CoA binding protein ACBP may modulate long-chain fatty acyl-CoA (LCFA-CoA) distribution, its physiological function in mammals is unresolved. To address this issue, the effect of ACBP on liver LCFA-CoA pool size, acyl chain composition, distribution, and transacylation into more complex lipids was examined in transgenic mice expressing a higher level of ACBP. While ACBP transgenic mice did not exhibit altered body or liver weight, liver LCFA-CoA pool size increased by 69%, preferentially in saturated and polyunsaturated, but not monounsaturated, LCFA-CoAs. Intracellular LCFA-CoA distribution was also altered such that the ratio of LCFA-CoA content in (membranes, organelles)/cytosol increased 2.7-fold, especially in microsomes but not mitochondria. The increased distribution of specific LCFA-CoAs to the membrane/organelle and microsomal fractions followed the same order as the relative LCFA-CoA binding affinity exhibited by murine recombinant ACBP: saturated > monounsaturated > polyunsaturated C14-C22 LCFA-CoAs. Consistent with the altered microsomal LCFA-CoA level and distribution, enzymatic activity of liver microsomal glycerol-3-phosphate acyltransferase (GPAT) increased 4-fold, liver mass of phospholipid and triacylglyceride increased nearly 2-fold, and relative content of monounsaturated C18:1 fatty acid increased 44% in liver phospholipids. These effects were not due to the ACBP transgene altering the protein levels of liver microsomal acyltransferase enzymes such as GPAT, lysophosphatidic acid acyltransferase (LAT), or acyl-CoA cholesterol acyltransferase 2 (ACAT-2). Thus, these data show for the first time in a physiological context that ACBP expression may play a role in LCFA-CoA metabolism.

Production of a Brassica napus Low-Molecular Mass Acyl-Coenzyme A-Binding Protein in Arabidopsis Alters the Acyl-Coenzyme A Pool and Acyl Composition of Oil in Seeds

“…7) is not surprising and was observed previously in both Saccharomyces cerevisiae and animal systems (Mandrup et al, 1993;Knudsen et al, 1994;Gaigg et al, 2001;Huang et al, 2005;Oikari et al, 2008). Indeed, the increase in the contribution of saturated acyl-CoAs to the total acyl-CoA pool observed in this study is similar to results reported in yeast and mice overexpressing ACBP (Mandrup et al, 1993;Huang et al, 2005).…”

“…7 and 8). In the case of ACBP lines, the increase in 18:2-CoA observed during late stages of seed development (20 DAF) could be explained by more efficient acyl editing of membrane phospholipids in the presence of higher ACBP levels (Huang et al, 2005;Yurchenko et al, 2009). It is also reasonable to speculate that enhanced channeling of 18:2 into TAG in these lines occurred, at least to some extent, via acyl-CoA-dependent pathways.…”

Disruption of the Acyl-CoA-binding Protein Gene Delays Hepatic Adaptation to Metabolic Changes at Weaning

“…In 3T3-L1 preadipocytes, knockdown of ACBP caused a mild impairment of adipocyte differentiation and accumulation of triacylglycerol (TAG) (27), whereas overexpression of ACBP in McA-RH7777 rat hepatoma cells resulted in increased intracellular TAG accumulation (29). Overexpression of ACBP in transgenic mice resulted in accumulation of different lipid classes, including TAG in the liver (30). These results suggest that ACBP may play a role in TAG synthesis.…”

“…We therefore consider it most likely that a decreased turnover of hepatic CE causes an increase in hepatic CE in ACBP Ϫ/Ϫ . Ectopic expression of ACBP in yeast (66,67) and mouse and rat liver (30,31) has been reported to increase the intracellular acyl-CoA level, indicating that ACBP is an acyl-CoA pool former. Curiously, however, the total acyl-CoA pool was unaffected in yeast by depletion of ACBP due to a general decrease in most acyl-CoA ester species accompanied by a significant increase in C18:0 acyl-CoA (24).…”

“…Ectopic expression of ACBP has been shown to increase the acyl-CoA pool size in yeast (66,67) and in mouse and rat liver (30,31). We therefore determined the level of acyl-CoA esters in livers from ACBP Ϫ/Ϫ and ACBP ϩ/ϩ mice.…”