Sequential ordered fatty acid alpha oxidation and Delta9 desaturation are major determinants of lipid storage and utilization in differentiating adipocytes.
Herein, we exploit the power of global lipidomics to identify the critical role of peroxisomal processing of fatty acids in adipocyte lipid storage and metabolism. Remarkably, 3T3-L1 differentiating adipocytes rapidly acquired the ability to alpha oxidize unbranched fatty acids, which is manifested in the accumulation of odd chain length unbranched fatty acids in all major lipid classes. Moreover, in differentiating adipocytes, unsaturated odd chain length fatty acids in TAG molecular species contained exclusively Delta9 olefinic linkages. Unsaturated fatty acids (e.g., oleic and palmitoleic acids) were not subject to alpha oxidation, resulting in the absence of Delta8 unsaturated odd chain length fatty acids. This highly selective substrate utilization resulted in the obligatory sequential ordering of alpha oxidation prior to Delta9 desaturation. On the basis of these results, a putative type 2 peroxisomal localization sequence was identified at the N-terminus of mouse stearoyl-CoA desaturase I (SCD I) comprised of (30)KVKTVPLHL(38). Kinetic analysis demonstrated that the rate of alpha oxidation of exogenously administered [9,10-(3)H]palmitic acid increased 4-fold during differentiation. Similarly, quantitative PCR demonstrated a 4-fold increase in phytanoyl-CoA alpha hydroxylase (PAHX) and fatty acyl-CoA oxidase (FACO) mRNA levels during differentiation. Collectively, these results underscore the role of peroxisomal fatty acid processing as an important determinant of the metabolic fate of fatty acids in the differentiating adipocyte.
Su
Xiong
X
Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Han
Xianlin
X
Yang
Jingyue
J
Mancuso
David J
DJ
Chen
Jeannie
J
Bickel
Perry E
PE
Gross
Richard W
RW
D041721:3T3-L1 Cells; D042962:Acyl-CoA Oxidase / Q000096:biosynthesis; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002250:Carbon Radioisotopes; D002454:Cell Differentiation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D007150:Immunohistochemistry; D007700:Kinetics; D051379:Mice; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism* / Q000494:pharmacology; D020675:Peroxisomes / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D021241:Spectrometry, Mass, Electrospray Ionization; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism*; D013379:Substrate Specificity; D014316:Tritium / Q000493:pharmacokinetics
D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D012333:RNA, Messenger; D014316:Tritium; D019308:Palmitic Acid; D006899:Mixed Function Oxygenases; C491170:Phyh protein, mouse; D013230:Stearoyl-CoA Desaturase; D042962:Acyl-CoA Oxidase