WDR76 mediates obesity and hepatic steatosis via HRas destabilization

Jong-Chan Park,Seol Hwa Seo,Woo-Jeong Jeong,Kang-Yell Choi

doi:10.1038/s41598-019-56211-6

Jong-Chan Park, Seol Hwa Seo + Show 2 more

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https://doi.org/10.1038/s41598-019-56211-6

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Journal: Scientific Reports	Publication Date: Dec 1, 2019
Citations: 10	License type: open-access

Affiliation: Yonsei University

Abstract

Ras/MAPK (mitogen active protein kinase) signaling plays contradictory roles in adipocyte differentiation and is tightly regulated during adipogenesis. However, mechanisms regulating adipocyte differentiation involving Ras protein stability regulation are unknown. Here, we show that WD40 repeat protein 76 (WDR76), a novel Ras regulating E3 linker protein, controls 3T3-L1 adipocyte differentiation through HRas stability regulation. The roles of WDR76 in obesity and metabolic regulation were characterized using a high-fat diet (HFD)-induced obesity model using Wdr76−/− mice and liver-specific Wdr76 transgenic mice (Wdr76Li−TG). Wdr76−/− mice are resistant to HFD-induced obesity, insulin resistance and hyperlipidemia with an increment of HRas levels. In contrast, Wdr76Li-TG mice showed increased HFD-induced obesity, insulin resistance with reduced HRas levels. Our findings suggest that WDR76 controls HFD-induced obesity and hepatic steatosis via HRas destabilization. These data provide insights into the links between WDR76, HRas, and obesity.

Highlights

Ras/MAPK signaling plays contradictory roles in adipocyte differentiation and is tightly regulated during adipogenesis
When fed a high-fat diet (HFD), mice deficient in hepatic ERK2 have increased levels of triglycerides in the liver leading to the development of hepatic steatosis[11]
To elucidate the role of WD40 repeat protein 76 (WDR76) on HRas protein stability during adipogenesis, we examined the effect of the knockdown or overexpression of WDR76 in 3T3-L1 cells

Summary

Introduction

Ras/MAPK (mitogen active protein kinase) signaling plays contradictory roles in adipocyte differentiation and is tightly regulated during adipogenesis. Wdr76Li-TG mice showed increased HFD-induced obesity, insulin resistance with reduced HRas levels. Our findings suggest that WDR76 controls HFD-induced obesity and hepatic steatosis via HRas destabilization. Dysregulation of hepatic lipid metabolism is related to hepatic steatosis (fatty liver), which results in chronic insulin resistance[8]. The Ras/ERK pathway plays important roles in adipogenesis via many functions from early to late adipocyte differentiation[14]. The Ras/ERK pathway plays important roles in the processes that regulate hepatic metabolism in response to insulin[10,11]. When fed a high-fat diet (HFD), mice deficient in hepatic ERK2 have increased levels of triglycerides in the liver leading to the development of hepatic steatosis[11]. Stability regulation of Ras, as an alternate approach for control of Ras activity, plays important roles in pathophysiology[25,26,27,28,29,30,31,32,33,34]

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