WDR76 mediates obesity and hepatic steatosis via HRas destabilization

Jong Chan Park; Woo Jeong Jeong; Seol Hwa Seo; Kang Yell Choi

doi:10.1038/s41598-019-56211-6

WDR76 mediates obesity and hepatic steatosis via HRas destabilization

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

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

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 (Wdr76^Li−TG). Wdr76^−/− mice are resistant to HFD-induced obesity, insulin resistance and hyperlipidemia with an increment of HRas levels. In contrast, Wdr76^Li-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.

Original language	English
Article number	19676
Journal	Scientific reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-56211-6
Publication status	Published - 2019 Dec 1

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean Ministry of Science, ICT, and Future Planning (MSIP); 2015R1A2A1A05001873 and A Mid-Career Researcher Program National Research Lab (2019R1A2C3002751). J.C.P was supported by a postdoctoral fellowship from the NRF (NRF-2017R1A6A3A01012866).

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© 2019, The Author(s).

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title = "WDR76 mediates obesity and hepatic steatosis via HRas destabilization",

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.",

author = "Park, {Jong Chan} and Jeong, {Woo Jeong} and Seo, {Seol Hwa} and Choi, {Kang Yell}",

note = "Funding Information: This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean Ministry of Science, ICT, and Future Planning (MSIP); 2015R1A2A1A05001873 and A Mid-Career Researcher Program National Research Lab (2019R1A2C3002751). J.C.P was supported by a postdoctoral fellowship from the NRF (NRF-2017R1A6A3A01012866). Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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AU - Park, Jong Chan

AU - Jeong, Woo Jeong

AU - Seo, Seol Hwa

AU - Choi, Kang Yell

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PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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WDR76 mediates obesity and hepatic steatosis via HRas destabilization

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