2. Academic Validation
  3. Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex

Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex

  • Cell Rep. 2022 Oct 18;41(3):111498. doi: 10.1016/j.celrep.2022.111498.
Liping Xie 1,  Yanmei Yuan 1,  Simiao Xu 2,  Sijia Lu 1,  Jinyang Gu 3,  Yanping Wang 1,  Yibing Wang 4,  Xianjing Zhang 1,  Suzhen Chen 1,  Jian Li 1,  Junxi Lu 1,  Honglin Sun 1,  Ruixiang Hu 5,  Hailong Piao 6,  Wen Wang 6,  Cunchuan Wang 7,  Jing Wang 8,  Na Li 8,  Morris F White 9,  Liu Han 1,  Weiping Jia 1,  Ji Miao 10,  Junli Liu 11
Affiliations

Affiliations

  • 1 Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
  • 2 Division of Endocrinology, Boston Children's Hospital, Boston, MA 02215, USA; Division of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Branch of National Clinical Research Center for Metabolic Disease, Wuhan, Hubei 430030, China.
  • 3 Department of Transplantation, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200042, China.
  • 4 School of Kinesiology, Shanghai University of Sports, Shanghai 200438, China.
  • 5 Division of Endocrinology, Boston Children's Hospital, Boston, MA 02215, USA; Department of Gastrointestinal Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China.
  • 6 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China.
  • 7 Department of Gastrointestinal Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China.
  • 8 State Key Laboratory of Natural and Biomimetic Drugs Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • 9 Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
  • 10 Division of Endocrinology, Boston Children's Hospital, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
  • 11 Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China. Electronic address: [email protected].
PMID: 36261001 DOI: 10.1016/j.celrep.2022.111498
Abstract

Copper deficiency has emerged to be associated with various lipid metabolism diseases, including non-alcoholic fatty liver disease (NAFLD). However, the mechanisms that dictate the association between copper deficiency and metabolic diseases remain obscure. Here, we reveal that copper restoration caused by hepatic ceruloplasmin (Cp) ablation enhances lipid catabolism by promoting the assembly of copper-load SCO1-LKB1-AMPK complex. Overnutrition-mediated Cp elevation results in hepatic copper loss, whereas Cp ablation restores copper content to the normal level without eliciting detectable hepatotoxicity and ameliorates NAFLD in mice. Mechanistically, SCO1 constitutively interacts with LKB1 even in the absence of copper, and copper-loaded SCO1 directly tethers LKB1 to AMPK, thereby activating AMPK and consequently promoting mitochondrial biogenesis and fatty acid oxidation. Therefore, this study reveals a mechanism by which copper, as a signaling molecule, improves hepatic lipid catabolism, and it indicates that targeting copper-SCO1-AMPK signaling pathway ameliorates NAFLD development by modulating AMPK activity.

Keywords

AMPK; CP: Metabolism; NAFLD; ceruloplasmin; copper sensing; fatty acid oxidation; metabolism; mitochondrial biogenesis.

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