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CELSR2 deficiency suppresses lipid accumulation in hepatocyte by impairing the UPR and elevating ROS level

Junyang Tan1,2, Yaping Che2, Yanyan Liu2

  • 1Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|September 3, 2021
PubMed

Insights

Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2) deficiency reduces liver lipid accumulation and impairs unfolded protein response (UPR). This suggests CELSR2 is a potential therapeutic target for non-alcoholic fatty liver disease (NAFLD).

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Hepatology

Background:

  • Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2) is involved in neural development and cilium polarity.
  • CELSR2 gene variations are linked to coronary artery disease, scoliosis, and cancer.
  • The role of CELSR2 in hepatic lipid metabolism is currently unknown.

Purpose of the Study:

  • To investigate the function and mechanism of CELSR2 in hepatic lipid metabolism.
  • To determine the effect of CELSR2 on non-alcoholic fatty liver disease (NAFLD).

Main Methods:

  • Analysis of CELSR2 expression in liver samples from NAFLD/NASH patients and db/db mice.
  • In vitro studies involving hepatocyte lipid accumulation, gene expression analysis, and unfolded protein response (UPR) assessment.
  • Evaluation of reactive oxygen species (ROS) levels and cell survival following CELSR2 manipulation.
  • Treatment with N-acetylcysteine to assess ROS scavenging effects.

Main Results:

  • CELSR2 expression is decreased in the livers of NAFLD/NASH patients and db/db mice.
  • CELSR2 depletion reduces lipid accumulation in hepatocytes by suppressing lipid synthesis enzymes.
  • CELSR2 deficiency impairs UPR, damages ER homeostasis, and increases ROS levels.
  • CELSR2 loss affects cell survival by reducing proliferation and increasing apoptosis.

Conclusions:

  • CELSR2 plays a significant role in regulating hepatic lipid homeostasis and UPR.
  • CELSR2 deficiency exacerbates NAFLD pathogenesis by disrupting ER homeostasis and increasing oxidative stress.
  • CELSR2 represents a potential therapeutic target for non-alcoholic fatty liver disease.
Keywords:
CELSR2cell survivallipid metabolismunfolded protein response

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