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.

β-Klotho deficiency protects against obesity through a crosstalk between liver, microbiota, and brown adipose tissue

“…We now demonstrate that global β-klotho deficiency elevated thermogenesis and BAT activity on HFD, underlying a resistance to obesity. Our results are in accordance with a recent report showing limited weight gain in Klb -/-mice on HFD without mechanistic explanation of the observed phenomenon (18).…”

“…Before HFD initiation, body weights (BWs) of Klb -/-mice on a pure C57BL/6J background were approximately 15% lower than WT littermates at 10 weeks of age ( Figure 1A, first time point). This reduced BW in basal conditions was similarly reported on a mixed genetic background, reflecting an isometric growth limitation with no change in adiposity (17,18). Klb -/-mice gain less weight than WT on HFD ( Figure 1A), exhibiting a massive limitation in fat mass accretion ( Figure 1B).…”

“…Recent data demonstrate that reexpression of Klb specifically in hepatocyte reverses the lipid dysregulations and normalizes BA metabolism in Klb -/-mice (18). Klb -/-mice exhibited a normal energy balance on standard chow diet (17,18).…”

Fgf21 regulates T-cell development in the neonatal and juvenile thymus

“…To investigate whether β-Klotho was involved in the functions of Fgf21 in the thymus, we examined the population of thymocytes and splenocytes from Klb −/− mice. As shown previously 20 , the body weight of Klb −/− mice was smaller than that of Klb +/− mice (Fig. 5A), and tissue weights and cellularity of the thymus and spleen, accordingly, had decreased tendencies especially in 1-week-old Klb −/− mice (Fig.…”

Arabinoxylan activates lipid catabolism and alleviates liver damage in rats induced by high‐fat diet

“…However, the effect of arabinoxylan on the liver damage induced by high‐fat diet need further exploiting. A rodent is generally accepted as a suitable lipid metabolic model for human . Therefore, the objective of the present study was to determine the effect of arabinoxylan on lipid metabolism and liver damage in rats induced by high‐fat diet.…”