Ahnak deficiency attenuates high-fat diet-induced fatty liver in mice through FGF21 induction

Yo Na Kim,Dong Soo Kyeong,Mi-Ock Lee,Jae Hoon Shin,Yun Soo Bae,Il Yong Kim,Je Kyung Seong,Soo Young Cho,Maria Raquel Rojas Jimenez,Mi-Young Kim,Hee Jung Lim

doi:10.1038/s12276-021-00573-3

Abstract

The AHNAK nucleoprotein has been determined to exert an anti-obesity effect in adipose tissue and further inhibit adipogenic differentiation. In this study, we examined the role of AHNAK in regulating hepatic lipid metabolism to prevent diet-induced fatty liver. Ahnak KO mice have reportedly exhibited reduced fat accumulation in the liver and decreased serum triglyceride (TG) levels when provided with either a normal chow diet or a high-fat diet (HFD). Gene expression profiling was used to identify novel factors that could be modulated by genetic manipulation of the Ahnak gene. The results revealed that fibroblast growth factor 21 (FGF21) was markedly increased in the livers of Ahnak KO mice compared with WT mice fed a HFD. Ahnak knockdown in hepatocytes reportedly prevented excessive lipid accumulation induced by palmitate treatment and was associated with increased secretion of FGF21 and the expression of genes involved in fatty acid oxidation, which are primarily downstream of PPARα. These results indicate that pronounced obesity and hepatic steatosis are attenuated in HFD-fed Ahnak KO mice. This may be attributed, in part, to the induction of FGF21 and regulation of lipid metabolism, which are considered to be involved in increased fatty acid oxidation and reduced lipogenesis in the liver. These findings suggest that targeting AHNAK may have beneficial implications in preventing or treating hepatic steatosis.

Highlights

Nonalcoholic fatty liver disease (NAFLD) has been identified as a common disorder that is characterized by increased hepatic triglyceride (TG) accumulation
Ahnak KO mice are resistant to high-fat diet (HFD)-induced hepatic steatosis
Histological analysis revealed that WT mice receiving a HFD exhibited severe hepatic steatosis with an accumulation of intracellular lipid droplets, whereas Ahnak KO mice did not display fatty liver symptoms (Fig. 1c)

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) has been identified as a common disorder that is characterized by increased hepatic triglyceride (TG) accumulation. Hepatic lipid accumulation is known to be regulated by lipid uptake, de novo synthesis, oxidation, and transport of fatty acids to the circulation[2]. FGF21 is primarily synthesized and secreted from the liver[4], and the action of circulating FGF21 is mediated through FGF receptors complexed with β-Klotho[5]. The expression of Fgf[21] is induced by the activation of peroxisome proliferatoractivated receptor alpha (PPARα). Nonesterified fatty acids bind to and activate PPARα. Ligand-bound PPARα forms a heterodimer with retinoid X receptors to induce the expression of Fgf[21]. FGF21 signaling is transduced by activating the β-Klotho-

Methods

Results

Conclusion