Hepatocyte β-Klotho regulates lipid homeostasis but not body weight in mice.

Kanako Kobayashi; Tomohiro Tanaka; Sadanori Okada; Yuki Morimoto; Shigenobu Matsumura; Manio, Mark Christian C.; Kazuo Inoue; Kumi Kimura; Takashi Yagi; Yoshihiko Saito; Tohru Fushiki; Hiroshi Inoue; Michihiro Matsumoto; Yo-ichi Nabeshima

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-klsolely in hepatocytes (β-kl-/-/Tg). Gene expression, metabolomic, and in vivoflux 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.

LIVER cells; HOMEOSTASIS; BODY weight; LABORATORY mice; MEMBRANE proteins; PROTEIN expression; BILE acids

FASEB Journal, 2016, Vol 30, Issue 2, p849

0892-6638

Academic Journal

10.1096/fj.15-274449