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  3. A bacteria-derived tetramerized protein ameliorates nonalcoholic steatohepatitis in mice via binding and relocating acetyl-coA carboxylase

A bacteria-derived tetramerized protein ameliorates nonalcoholic steatohepatitis in mice via binding and relocating acetyl-coA carboxylase

  • Cell Rep. 2023 Nov 16;42(11):113453. doi: 10.1016/j.celrep.2023.113453.
Yan Lin 1,  Mingkun Yang 2,  Li Huang 3,  Fan Yang 1,  Jiachen Fan 1,  Yulong Qiang 1,  Yuting Chang 1,  Wenjie Zhou 1,  Leilei Yan 1,  Jie Xiong 4,  Jie Ping 5,  Shizhen Chen 6,  Dong Men 7,  Feng Li 8
Affiliations

Affiliations

  • 1 Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China.
  • 2 State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
  • 3 Research Center for Medicine and Structural Biology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China.
  • 4 Department of Immunology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China.
  • 5 Department of Pharmacology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China.
  • 6 State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, China.
  • 7 Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou 510005, Guangdong Province, China. Electronic address: men_dong@gzlab.ac.cn.
  • 8 Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Allergy and Immunology, Wuhan 430071, China. Electronic address: fli222@whu.edu.cn.
PMID: 37976162 DOI: 10.1016/j.celrep.2023.113453
Abstract

Increased de novo lipogenesis (DNL) is a major feature of nonalcoholic steatohepatitis (NASH). None of the drugs targeting the catalytic activity of Acetyl-CoA Carboxylase (ACC), the rate-limiting Enzyme in the DNL process, have been approved by the FDA. Whether cytosolic ACC1 can be regulated spatially remains to be explored. Herein, we find that streptavidin (SA), which is a bacterium-derived tetrameric protein, forms cytosolic condensates and efficiently induces a spatial re-localization of ACC1 in liver cells, concomitant with inhibited lipid accumulation. Both SA tetrameric structure and multivalent protein interaction are required for condensate formation. Interestingly, the condensates are further characterized as gel-like membraneless organelle (SAGMO) and significantly restrict the cytosolic dispersion of ACC1 and fatty acid synthase. Notably, AAV-mediated delivery of SA partially blocks mouse liver DNL and ameliorates NASH without eliciting hypertriglyceridemia. In summary, our study shows that insulating lipogenesis-related proteins by SAGMO might be effective for NASH treatment.

Keywords

CP: Metabolism; CP: Microbiology; acetyl-CoA carboxylase; de novo lipogenesis; membraneless organelle; nonalcoholic steatohepatitis; streptavidin.

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