Effect of SCP-x gene ablation on branched-chain fatty acid metabolism.
Despite the importance of peroxisomal oxidation in branched-chain lipid (phytol, cholesterol) detoxification, little is known regarding the factors regulating the peroxisomal uptake, targeting, and metabolism of these lipids. Although in vitro data suggest that sterol carrier protein (SCP)-x plays an important role in branched-chain lipid oxidation, the full physiological significance of this peroxisomal enzyme is not completely clear. To begin to resolve this issue, SCP-x-null mice were generated by gene ablation of SCP-x from the SCP-x/SCP-2 gene and fed a phytol-enriched diet to characterize the effects of lipid overload in a system with minimal 2/3-oxoacyl-CoA thiolytic activity. It was shown that SCP-x gene ablation 1) did not result in reduced expression of SCP-2 (previously thought to be derived in considerable part by posttranslational cleavage of SCP-x); 2) increased expression levels of key enzymes involved in alpha- and beta-oxidation; and 3) altered lipid distributions, leading to decreased hepatic fatty acid and triglyceride levels. In response to dietary phytol, lack of SCP-x resulted in 1) accumulation of phytol metabolites despite substantial upregulation of hepatic peroxisomal and mitochondrial enzymes; 2) reduced body weight gain and fat tissue mass; and 3) hepatic enlargement, increased mottling, and necrosis. In summary, the present work with SCP-x gene-ablated mice demonstrates, for the first time, a direct physiological relationship between lack of SCP-x and decreased ability to metabolize branched-chain lipids.
Atshaves
Barbara P
BP
Department of Physiology and Pharmacology, Texas A and M University, College Station, Texas 77843, USA.
McIntosh
Avery L
AL
Landrock
Danilo
D
Payne
H Ross
HR
Mackie
John T
JT
Maeda
Nobuyo
N
Ball
Judith
J
Schroeder
Friedhelm
F
Kier
Ann B
AB
D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D019883:Alkyl and Aryl Transferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D050218:Body Fat Distribution; D001835:Body Weight / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D050612:Fatty Acid Transport Proteins / Q000378:metabolism; D005227:Fatty Acids / Q000032:analysis / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000032:analysis / Q000097:blood / Q000737:chemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D020675:Peroxisomes / Q000187:drug effects / Q000201:enzymology; D010831:Phytanic Acid / Q000378:metabolism; D010836:Phytol / Q000378:metabolism / Q000494:pharmacology; D012737:Sex Factors
D002352:Carrier Proteins; D050612:Fatty Acid Transport Proteins; D005227:Fatty Acids; D008055:Lipids; C072087:sterol carrier proteins; D010831:Phytanic Acid; D010836:Phytol; C002844:pristanic acid; D000101:Acetyl-CoA C-Acetyltransferase; D019883:Alkyl and Aryl Transferases; C112459:geranylpyrophosphate olivetolate geranyltransferase