title: Hepatocyte β-Klotho regulates lipid homeostasis but not body weight in mice.
abstract: 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.
authors.affiliation: *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.
authors.forename: Kanako
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: *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.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: *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.
authors.forename: Sadanori
authors.initials: S
authors.lastname: Okada
authors.affiliation: *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.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Morimoto
authors.affiliation: *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.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Matsumura
authors.affiliation: *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.
authors.forename: Mark Christian C
authors.initials: MC
authors.lastname: Manio
authors.affiliation: *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.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Inoue
authors.affiliation: *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.
authors.forename: Kumi
authors.initials: K
authors.lastname: Kimura
authors.affiliation: *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.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yagi
authors.affiliation: *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.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Saito
authors.affiliation: *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.
authors.forename: Tohru
authors.initials: T
authors.lastname: Fushiki
authors.affiliation: *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.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.affiliation: *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.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: *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 nabemr@lmls-kobe.org.
authors.forename: Yo-Ichi
authors.initials: Y
authors.lastname: Nabeshima
mesh_terms: D000818:Animals; D001835:Body Weight / Q000502:physiology*; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D000090265:Klotho Proteins; D050356:Lipid Metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism
chemical_list: C418622:Klb protein, mouse; D008565:Membrane Proteins; D002784:Cholesterol; D000090265:Klotho Proteins
keywords: bile acid; cholesterol; fibroblast growth factor; metabolomics; triglyceride