2. Academic Validation
  3. Hepatic ER stress suppresses adipose browning through ATF4-CIRP-ANGPTL3 cascade

Hepatic ER stress suppresses adipose browning through ATF4-CIRP-ANGPTL3 cascade

  • Cell Rep. 2022 Sep 27;40(13):111422. doi: 10.1016/j.celrep.2022.111422.
Sihan Lv 1,  Yingqun Zhou 2,  Jiaojiao Chen 3,  Huiwen Yuan 1,  Zhen-Ning Zhang 4,  Bing Luan 5
Affiliations

Affiliations

  • 1 Department of Endocrinology, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai 200072, China.
  • 2 Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China.
  • 3 Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China; School of Clinical Medicine, Nanjing Medical University, Nanjing 211166, China.
  • 4 Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China.
  • 5 Department of Endocrinology, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai 200072, China. Electronic address: bluan@tongji.edu.cn.
PMID: 36170814 DOI: 10.1016/j.celrep.2022.111422
Abstract

Hepatic endoplasmic reticulum (ER) stress is a hallmark of obesity-induced liver steatosis and contributes to the progress of steatosis and Insulin resistance in liver. However, its influence on adipose function is still unclear. Here, we identify a hepatic ER stress-induced activating transcription factor 4 (ATF4)-cold-inducible RNA-binding protein (CIRP)-angiopoietin-related protein3 (ANGPTL3) cascade critical for the regulation of adipose browning. We find that obesity increases CIRP expression in liver through ER stress-induced ATF4. CIRP in turn binds to the 3' UTR and increases mRNA stability of ANGPTL3. ANGPTL3 secreted from liver suppresses uncoupling protein 1 expression through Integrin αvβ3 and c-Jun N-terminal kinase in adipose tissue. While hepatic expression of either ATF4, CIRP, or ANGPTL3 suppresses adipose browning, knockdown of CIRP and ANGPTL3 in liver or administration of Integrin αvβ3 inhibitor cilengitide increases adipose browning process. Taken together, we identify a communication mechanism to link hepatic ER stress and adipose browning that may imply a reciprocal regulation of obesity and liver steatosis.

Keywords

ANGPTL3; ATF4; CIRP; CP: Metabolism; adipose browning; hepatic ER stress.

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