Decreased Fatty Acid β-Oxidation Is the Main Cause of Fatty Liver Induced by Polyunsaturated Fatty Acid Deficiency in Mice

Decreased Fatty Acid β-Oxidation Is the Main Cause of Fatty Liver Induced by Polyunsaturated Fatty Acid Deficiency in Mice

TAKERO NAKAJIMA,^1,2 YANG YANG,^1,3 YU LU,¹ YUJI KAMIJO,^1,4 YOSUKE YAMADA,^1,4 KOZO NAKAMURA,^2,5 MASAHIRO KOYAMA,⁵ SHOHEI YAMAGUCHI,⁵ EIKO SUGIYAMA,⁶ NAOKI TANAKA^1,2 and TOSHIFUMI AOYAMA¹

¹Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan
²Research Center for Agricultural Food Industry, Shinshu University, Matsumoto, Nagano, Japan
³Department of Cardiology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, P.R. China
⁴Department of Nephrology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
⁵Department of Bioscience and Biotechnology, Faculty of Agriculture, Shinshu University, Kamiina-gun, Nagano, Japan
⁶Department of Nutritional Science, Nagano Prefectural College, Nagano, Nagano, Japan

Insufficient intake of polyunsaturated fatty acids (PUFA) causes fatty liver. The mechanism responsible is primarily related to increased lipogenesis and decreased FA degradation based on rodent studies. However, these studies were limited by the fact that the typical PUFA-deficient diets contained insufficient amounts of long-chain FA, the PUFA-containing diets were primarily composed of n-3 PUFA-enriched oil, and the intake of PUFA was excessive compared with the physiological requirement. To address these issues, mice were fed a PUFA-deficient diet containing long-chain FA at a standard fed level and then were orally fed a n-3/n-6-balanced PUFA-containing oil [PUFA (+)] or a PUFA-deficient oil [PUFA (−)] at physiological relevant levels (0.1 mL/mouse/2d). We compared these groups and examined whether fatty liver in PUFA deficiency was attributable to both the effects of increased lipogenesis and decreased FA catabolism. Compared with the PUFA (+) group, the PUFA (−) group showed increases in liver triglyceride and serum FA content. Hepatic gene expression of several mitochondrial β-oxidation enzymes, the serum 3-hydroxybutyrate level, and DNA-binding ability of peroxisome proliferator-activated receptor α (PPARα) were increased in the PUFA (+) group, whereas these adaptive responses were significantly attenuated in the PUFA (−) group. The hepatic expression of typical lipogenesis genes did not differ between the groups. Therefore, fatty liver in PUFA deficiency is attributable to suppression of the FA-degrading system probably from decreased PPARα adaptive responsiveness, and PUFA may be an essential factor for PPARα functioning. This finding is helpful for managing clinical situations having a risk of PUFA deficiency.

keywords —— essential fatty acid deficiency; fatty acid metabolism; fatty liver; peroxisome proliferator-activated receptor α; polyunsaturated fatty acids

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Tohoku J. Exp. Med., 2017, 242, 229-239

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