Kobayashi Kanako, Tanaka Tomohiro, Okada Sadanori, Morimoto Yuki, Matsumura Shigenobu, Manio Mark Christian C, Inoue Kazuo, Kimura Kumi, Yagi Takashi, Saito Yoshihiko, Fushiki Tohru, Inoue Hiroshi, Matsumoto Michihiro, Nabeshima Yo-Ichi
*Laboratory of Molecular Life Science, Foundation for Biomedical Research and Innovation, Kobe, Hyogo, Japan; Medical Innovation Center and Department of Pathology and Tumor Biology, Graduate School of Medicine, and Laboratory of Nutrition Chemistry, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto, Japan; First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan; Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan; and Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan.
*Laboratory of Molecular Life Science, Foundation for Biomedical Research and Innovation, Kobe, Hyogo, Japan; Medical Innovation Center and Department of Pathology and Tumor Biology, Graduate School of Medicine, and Laboratory of Nutrition Chemistry, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto, Japan; First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan; Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan; and Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan
FASEB J. 2016 Feb;30(2):849-62. doi: 10.1096/fj.15-274449. Epub 2015 Oct 29.
β-Klotho (β-Kl), a transmembrane protein expressed in the liver, pancreas, adipose tissues, and brain, is essential for feedback suppression of hepatic bile acid synthesis. Because bile acid is a key regulator of lipid and energy metabolism, we hypothesized potential and tissue-specific roles of β-Kl in regulating plasma lipid levels and body weight. By crossing β-kl(-/-) mice with newly developed hepatocyte-specific β-kl transgenic (Tg) mice, we generated mice expressing β-kl solely in hepatocytes (β-kl(-/-)/Tg). Gene expression, metabolomic, and in vivo flux analyses consistently revealed that plasma level of cholesterol, which is over-excreted into feces as bile acids in β-kl(-/-), is maintained in β-kl(-/-) mice by enhanced de novo cholesterogenesis. No compensatory increase in lipogenesis was observed, despite markedly decreased plasma triglyceride. Along with enhanced bile acid synthesis, these lipid dysregulations in β-kl(-/-) were completely reversed in β-kl(-/-)/Tg mice. In contrast, reduced body weight and resistance to diet-induced obesity in β-kl(-/-) mice were not reversed by hepatocyte-specific restoration of β-Kl expression. We conclude that β-Kl in hepatocytes is necessary and sufficient for lipid homeostasis, whereas nonhepatic β-Kl regulates energy metabolism. We further demonstrate that in a condition with excessive cholesterol disposal, a robust compensatory mechanism maintains cholesterol levels but not triglyceride levels in mice.
β-klotho（β-Kl）是一种在肝脏、胰腺、脂肪组织和大脑中表达的跨膜蛋白，对肝脏胆汁酸合成的反馈抑制至关重要。由于胆汁酸是脂质和能量代谢的关键调节因子，我们推测β-Kl在调节血脂水平和体重方面具有潜在的组织特异性作用。通过将β-kl（-/-）小鼠与新开发的肝细胞特异性β-kl转基因（Tg）小鼠杂交，我们培育出仅在肝细胞中表达β-kl的小鼠（β-kl（-/-）/Tg）。基因表达、代谢组学和体内通量分析一致显示，在β-kl（-/-）中作为胆汁酸过度排泄到粪便中的胆固醇血浆水平，在β-kl（-/-）小鼠中通过增强的从头胆固醇生物合成得以维持。尽管血浆甘油三酯明显降低，但未观察到脂肪生成的代偿性增加。随着胆汁酸合成的增强，β-kl（-/-）中的这些脂质失调在β-kl（-/-）/Tg小鼠中完全逆转。相比之下，β-kl（-/-）小鼠体重减轻和对饮食诱导肥胖的抵抗力并未因肝细胞特异性恢复β-Kl表达而逆转。我们得出结论，肝细胞中的β-Kl对于脂质稳态是必要且充分的，而非肝脏中的β-Kl调节能量代谢。我们进一步证明，在胆固醇处置过多的情况下，一种强大的代偿机制可维持小鼠的胆固醇水平，但不能维持甘油三酯水平。
