Tohoku J. Exp. Med., 2016 October, 240(2)

Activation of PPARα by Fatty Acid Accumulation Enhances Fatty Acid Degradation and Sulfatide Synthesis

YANG YANG,¹ YUYAO FENG,¹ XIAOWEI ZHANG,² TAKERO NAKAJIMA,¹ NAOKI TANAKA,¹ EIKO SUGIYAMA,³ YUJI KAMIJO⁴ and TOSHIFUMI AOYAMA¹

¹Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan
²Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
³Department of Nutritional Science, Nagano Prefectural College, Nagano, Nagano, Japan
⁴Department of Nephrology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan

Very-long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the first reaction in the mitochondrial fatty acid β-oxidation pathway. VLCAD deficiency is associated with the accumulation of fat in multiple organs and tissues, which results in specific clinical features including cardiomyopathy, cardiomegaly, muscle weakness, and hepatic dysfunction in infants. We speculated that the abnormal fatty acid metabolism in VLCAD-deficient individuals might cause cell necrosis by fatty acid toxicity. The accumulation of fatty acids may activate peroxisome proliferator-activated receptor (PPAR), a master regulator of fatty acid metabolism and a potent nuclear receptor for free fatty acids. We examined six skin fibroblast lines, derived from VLCAD-deficient patients and identified fatty acid accumulation and PPARα activation in these cell lines. We then found that the expression levels of three enzymes involved in fatty acid degradation, including long-chain acyl-CoA synthetase (LACS), were increased in a PPARα-dependent manner. This increased expression of LACS might enhance the fatty acyl-CoA supply to fatty acid degradation and sulfatide synthesis pathways. In fact, the first and last reactions in the sulfatide synthesis pathway are regulated by PPARα. Therefore, we also measured the expression levels of enzymes involved in sulfatide metabolism and the regulation of cellular sulfatide content. The levels of these enzymes and cellular sulfatide content both increased in a PPARα-dependent manner. These results indicate that PPARα activation plays defensive and compensative roles by reducing cellular toxicity associated with fatty acids and sulfuric acid.

keywords —— cerebroside sulfotransferase; peroxisome proliferator-activated receptor α; serine palmitoyl-CoA transferase; sulfatides; very-long-chain acyl-CoA dehydrogenase

© 2016 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2016, 240, 113-122

Correspondence: Yuji Kamijo, M.D., Ph.D., Department of Nephrology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.

e-mail: yujibeat@shinshu-u.ac.jp