Soluble Klotho Improves Hepatic Glucose and Lipid Homeostasis in Type 2 Diabetes

Abstract

Type 2 diabetes (T2D) is one of the most escalating global metabolic diseases, which is highly associated with insulin resistance (IR) and risk of combination with nonalcoholic fatty liver disease (NAFLD). Previous studies suggest that soluble klotho (sKL) could serve as a circulating hormone to mediate energy metabolism, but the detailed mechanism is poorly understood. In this study, we generated T2D models of wild-type (WT), sKL heterozygous ( KL +/− ), and sKL transgenic (Tg KL ) mice continuously fed a high-fat diet (HFD) and constructed L02 cell lines that stably overexpress sKL to investigate the effect of sKL on hepatic glucose and lipid metabolism. Surprisingly, we discovered that sKL deficiency resulted in exacerbated diabetic phenotypes and hepatic glucolipid metabolism disorders in HFD-fed KL +/− diabetic mice ( KL +/− DM), whereas TgKL diabetic mice (TgKL DM) exhibited ameliorated diabetic phenotypes and decreased IR. Mechanistic studies in vitro and in vivo demonstrated that sKL could inhibit the PI3K/AKT/mTORC1 signaling to upregulate peroxisome proliferator-activated receptor α (PPARα) expression by directly interacting with type 1 insulin-like growth factor receptor (IGF1R) in HFD-fed T2D mice. Thus, sKL could improve hepatic glucolipid homeostasis to ameliorate diabetic phenotypes and lipid accumulation and may function as a potential therapeutic target for the treatment of T2D and reduce the risk of NAFLD.

Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer

“…sKL inhibits insulin growth factor 1 receptor (IGF-1R)/phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling and activates forkhead box O (FOXO) ( Kurosu et al, 2005 ; Yamamoto et al, 2005 ). It increases glucose uptake and glycogen storage and reduces lipid accumulation and insulin resistance through PPARα expression ( Gu et al, 2020 ) corroborating the role of KL and underlying signaling in glucose metabolism and adipocyte maturation as discussed recently ( Razzaque, 2012 ). Other KL downstream effects are the activation of extracellular signal–related kinase 1/2 (ERK1/2) ( Maekawa et al, 2011 ), inhibition of Wnt signaling ( Liu et al, 2007 ), or reduction of inflammation ( Maekawa et al, 2009 ).…”

Association between Soluble α-Klotho Protein and Metabolic Syndrome in the Adult Population

“…CSF α-Klotho’s prominent role in energy balance was demonstrated by strong inverse correlations with body weight and an ability to increase energy expenditure [ 20 ]. Soluble Klotho improves hepatic glucolipid homeostasis to ameliorate diabetic phenotypes and lipid accumulation in the mice model with type 2 diabetes mellitus in comparing wild-type, soluble Klotho heterozygous, and soluble Klotho transgenic group [ 21 ]. Histological examination suggests that Klotho mice possess less energy storage than wild-type mice concerning glycogen in the liver and lipid in brown adipose tissue [ 22 ].…”

Protective association of Klotho rs495392 gene polymorphism against hepatic steatosis in non-alcoholic fatty liver disease patients

“…Nevertheless, the overexpression of sKL reversed these phenomena. 37 Rao et al found administration of Klotho resulted in decreased fat mass, increased lean mass and reduced lipid accumulation in liver of obese mice. 35 In addition to hepatic lipid accumulation, insulin resistance also plays a crucial role in fatty liver disease.…”

“…45 Moreover, PPAR-α was also reported to mediate the regulation of sKL on hepatic lipid metabolism in mice. 37 Genetic polymorphisms of Klotho gene were associated with various pathophysiological processes and diseases. [10][11][12][13] In our Chinese cohort, carriage of the KL rs495392 A allele was related to a lower risk of severe steatosis in patients with NAFLD, without affecting body mass nor insulin resistance.…”