| First Author | Kobayashi K | Year | 2016 |
| Journal | FASEB J | Volume | 30 |
| Issue | 2 | Pages | 849-62 |
| PubMed ID | 26514166 | Mgi Jnum | J:230843 |
| Mgi Id | MGI:5766123 | Doi | 10.1096/fj.15-274449 |
| Citation | Kobayashi K, et al. (2016) Hepatocyte beta-Klotho regulates lipid homeostasis but not body weight in mice. FASEB J 30(2):849-62 |
| abstractText | beta-Klotho (beta-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 beta-Kl in regulating plasma lipid levels and body weight. By crossing beta-kl(-/-) mice with newly developed hepatocyte-specific beta-kl transgenic (Tg) mice, we generated mice expressing beta-kl solely in hepatocytes (beta-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 beta-kl(-/-), is maintained in beta-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 beta-kl(-/-) were completely reversed in beta-kl(-/-)/Tg mice. In contrast, reduced body weight and resistance to diet-induced obesity in beta-kl(-/-) mice were not reversed by hepatocyte-specific restoration of beta-Kl expression. We conclude that beta-Kl in hepatocytes is necessary and sufficient for lipid homeostasis, whereas nonhepatic beta-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.-Kobayashi, K., Tanaka, T., Okada, S. Morimoto, Y., Matsumura, S., Manio, M. C. C., Inoue, K., Kimura, K., Yagi, T., Saito, Y., Fushiki, T., Inoue, H., Matsumoto, M., Nabeshima, Y. Hepatocyte beta-Klotho regulates lipid homeostasis but not body weight in mice. |
