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

Abstract

The mouse acyl-CoA-binding protein (ACBP) 5 /diazepam binding inhibitor is a 10-kDa intracellular protein consisting of 86 amino acids. It is highly conserved throughout evolution and expressed in all cell types in the eukaryotes investigated (1, 2). This, together with the characteristics of the ACBP promoter (3, 4), implies a housekeeping function of the gene. However, expression levels vary markedly between tissues (5) and in response to different metabolic stimuli (6 -9), thereby indicating that ACBP might perform more specialized functions in some cell types. The ACBP protein binds C 14 -C 22 acyl-CoA esters with high affinity and specificity (10, 11) and has very little or no affinity toward other ligands (11-13). From in vitro studies, ACBP is known to protect acyl-CoA esters from hydrolysis (14 -16) and to relieve acyl-CoA inhibition of a number of enzymes, including long chain acyl-CoA synthetase, acetyl-CoA carboxylase (ACC), adenine nucleotide translocase, fatty acid synthetase (FAS), carnitine palmitoyltransferase, and acyl-CoA:cholesterol acyltransferase (9, 16 -18). In addition, ACBP is known to donate acyl-CoA esters to phospholipid, glycerolipid, and cholesteryl ester (CE) synthesis (14, 18 -21). Finally, proteolytic products of secreted ACBP have been shown to have signaling functions in Dictyostelium as well as mammalian cells (22). Targeted disruption of the yeast ACBP gene (ACB1) revealed that ACBP deficiency results in increased levels of C18:0 acyl-CoA esters and a decrease in the amount of total C26:0 fatty acids, indicating that transport of FA toward elongation is impaired by lack of ACBP. Furthermore, sphingolipid and ceramide amounts were reduced, membrane structure was altered, and vesicular transport was compromised (23-25).The functions of ACBP in lipid metabolism have been further studied in different mammalian cell culture systems and animal models by both knockdown strategies and overexpression of the protein. It has been reported that knockdown of ACBP by small interfering RNA causes growth arrest and lethality in three different mammalian cell lines (26); however, data from our laboratory show that ACBP can be knocked down in many different cell systems without affecting growth and survival (27). 6 Recently, knockdown of ACBP in HepG2 cells was shown to suppress the expression of a number of genes involved in lipid biosynthesis and lead to decreased levels of saturated and monounsaturated fatty acids (28). 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 *

The acyl-CoA binding protein is required for normal epidermal barrier function in mice

“…Mice with targeted disruption of the ACBP gene were generated as described ( 24,29 ). Mice carrying the targeted ACBP gene were identifi ed using primer pairs i ) 5 ′ -AGG ATC TCC TGT CAT CTC ACC TTG CTC CTG and 5 ′ -AAG AAC TCG TCA AGA AGG CGA TAG AAG GCG ( ‫ف‬ 500 bp fragment within the neo R cassette) and ii ) 5 ′ -AGG ATC TCC TGT CAT CTC ACC TTG CTC CTG and 5 ′ -GTA TCT GCT CAT CTA TTC GGC TTG G ( ‫ف‬ 1,200 bp fragment spanning the 3 ′ region of the neo R cassette to the 5 ′ region of intron 2).…”

“…Recently, we reported specifi c targeting of the ACBP gene in C57BL/6JBomTac mice ( 24 ). ACBP Ϫ / Ϫ mice are viable and fertile and are born in a normal Mendelian ratio.…”

Current status and future perspectives: TSPO in steroid neuroendocrinology

“…As described previously, ACBP function is linked to lipid metabolism (Mandrup et al 1993, Gaigg et al 2001. These observations were confirmed in ACBP-knockout mice that indicate no role in steroid synthesis (Neess et al 2011, Bloksgaard et al 2012. Moreover, studies by independent groups could not confirm the TSPO-DBI interaction (Bogan et al 2007).…”

“…Loss of ACBP in these nm1054 mice was linked to fatty acid metabolism abnormalities in skin and hair ). The subsequent generation of viable Acbp-knockout mice (Acbp −/− ) displayed delayed metabolic adaptation to weaning (Neess et al 2011), and a phenotype of fatty acid metabolic abnormalities in skin and hair similar to nm1054 mutation (Bloksgaard et al 2012, Neess et al 2013. There was no phenotypic evidence that indicated defects in steroid hormone production in these Acbp −/− mice.…”

“…ACBP is involved in fatty acid metabolism , Neess et al 2011, and its expression mirrors TSPO in tissues (Tong et al 1991, Toranzo et al 1994. (2) Putative TSPO-VDAC1 interaction (McEnery et al 1992).…”