2. Academic Validation
  3. The GR-gp78 Pathway is involved in Hepatic Lipid Accumulation Induced by Overexpression of 11β-HSD1

The GR-gp78 Pathway is involved in Hepatic Lipid Accumulation Induced by Overexpression of 11β-HSD1

  • Int J Biol Sci. 2022 Apr 30;18(8):3107-3121. doi: 10.7150/ijbs.42376.
Mengliang Hu 1,  Tingting Han 1,  Qiyu Pan 1,  Dongsheng Ni 1 2,  Fengyi Gao 3 4,  Liying Wang 5 4,  Hangjiang Ren 1 2,  Xiaoyi Zhang 1 6,  Haoyun Jiao 1,  Yuefeng Wang 1,  Dapeng Dai 1,  Yong Man 1,  Weiqing Tang 1,  Yue Sun 7,  Wei Li 5 4,  Jian Li 1,  Guoping Li 1
Affiliations

Affiliations

  • 1 The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, P.R. China.
  • 2 Graduate School of Peking Union Medical College, Beijing 100730, P.R. China.
  • 3 College of Biology and Food, Shangqiu Normal University, Shangqiu, Henan 476000, P.R. China.
  • 4 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, P.R. China.
  • 5 Institute of Reproductive Health and Perinatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, P.R. China.
  • 6 Peking University Fifth School of Clinical Medicine (Beijing Hospital), Beijing 100730, P.R. China.
  • 7 Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
PMID: 35637957 DOI: 10.7150/ijbs.42376
Abstract

Glucocorticoids are essential participants in the regulation of lipid metabolism. On a tissue-specific level, glucocorticoid signal is controlled by 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1). Up-regulation of 11β-HSD1 expression during non-alcoholic fatty liver disease (NAFLD) has been previously shown, while 11β-HSD1 inhibition has been shown to reduce hepatic lipids in NAFLD, but the underlying mechanisms remain unclear. Here, in this study, we created in vitro Cell Culture and in vivo transgenic hepatocyte-specific 11β-HSD1 mouse models of NAFLD to determine the regulatory mechanisms of 11β-HSD1 during lipid metabolism dysfunction. We found that 11β-HSD1 overexpression activated glucocorticoid receptors and promoted their nuclear translocation, and then stimulating gp78. The induction of gp78 sharply reduced expression of Insig2, but not Insig1, which led to up-regulation of lipogenesis regulatory proteins including SREBP1, FAS, SCD1, and ACC1. Our results suggested that overexpression of 11β-HSD1 induced lipid accumulation, at least partially through the GR/gp78/Insig2/SREBP1 pathway, which may serve as a potential diagnostic and therapeutic target for treatment of NAFLD.

Keywords

11β-HSD1; Insig2/SREBP1; glucocorticoid receptor; gp78; non-alcoholic fatty liver disease..

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