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: Kanako Kobayashi, Tomohiro Tanaka, Sadanori Okada, Yuki Morimoto, Shigenobu Matsumura, Mark Christian C Manio, Kazuo Inoue, Kumi Kimura, Takashi Yagi, Yoshihiko Saito, Tohru Fushiki, Hiroshi Inoue, Michihiro Matsumoto, Yo-Ichi Nabeshima
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 30 Issue 2 Pg. 849-62 (Feb 2016) ISSN: 1530-6860 [Electronic] United States
• PMID: 26514166 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © FASEB.

Chemical References

• Klb protein, mouse
• Membrane Proteins
• Cholesterol
• Klotho Proteins

Topics

• Animals
• Body Weight (physiology)
• Cholesterol (genetics, metabolism)
• Energy Metabolism (physiology)
• Hepatocytes (cytology, metabolism)
• Klotho Proteins
• Lipid Metabolism (physiology)
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Knockout
• Obesity (genetics, metabolism)