1. Academic Validation
  2. TMEM41B acts as an ER scramblase required for lipoprotein biogenesis and lipid homeostasis

TMEM41B acts as an ER scramblase required for lipoprotein biogenesis and lipid homeostasis

  • Cell Metab. 2021 Aug 3;33(8):1655-1670.e8. doi: 10.1016/j.cmet.2021.05.006.
Dong Huang 1 Bolin Xu 1 Lu Liu 1 Lingzhi Wu 2 Yuangang Zhu 2 Alireza Ghanbarpour 3 Yawei Wang 4 Feng-Jung Chen 5 Jia Lyu 2 Yating Hu 2 Yunlu Kang 2 Wenjing Zhou 2 Xiao Wang 2 Wanqiu Ding 2 Xin Li 2 Zhaodi Jiang 6 Jizheng Chen 7 Xu Zhang 8 Hongwen Zhou 9 John Zhong Li 8 Chunguang Guo 2 Wen Zheng 2 Xiuqin Zhang 2 Peng Li 10 Thomas Melia 3 Karin Reinisch 3 Xiao-Wei Chen 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, Peking University, Beijing 100871, China; Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China.
  • 2 Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China.
  • 3 Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 4 Center for Life Sciences, Peking University, Beijing 100871, China.
  • 5 Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China.
  • 6 National Institute of Biological Sciences, Tsinghua University, Beijing 100086, China.
  • 7 Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510503, China.
  • 8 The Key Laboratory of Rare Metabolic Disease, Department of Biochemistry and Molecular Biology, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 9 Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
  • 10 Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China; School of Life Sciences, Tsinghua University, Beijing 100086, China.
  • 11 State Key Laboratory of Membrane Biology, Peking University, Beijing 100871, China; Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Center for Life Sciences, Peking University, Beijing 100871, China. Electronic address: [email protected].
Abstract

How amphipathic Phospholipids are shuttled between the membrane bilayer remains an essential but elusive process, particularly at the endoplasmic reticulum (ER). One prominent phospholipid shuttling process concerns the biogenesis of APOB-containing lipoproteins within the ER lumen, which may require bulk trans-bilayer movement of Phospholipids from the cytoplasmic leaflet of the ER bilayer. Here, we show that TMEM41B, present in the lipoprotein export machinery, encodes a previously conceptualized ER lipid scramblase mediating trans-bilayer shuttling of bulk Phospholipids. Loss of hepatic TMEM41B eliminates plasma lipids, due to complete absence of mature lipoproteins within the ER, but paradoxically also activates lipid production. Mechanistically, scramblase deficiency triggers unique ER morphological changes and unsuppressed activation of SREBPs, which potently promotes lipid synthesis despite stalled secretion. Together, this response induces full-blown nonalcoholic hepatosteatosis in the TMEM41B-deficient mice within weeks. Collectively, our data uncovered a fundamental mechanism safe-guarding ER function and integrity, dysfunction of which disrupts lipid homeostasis.

Keywords

SREBP; endoplasmic reticulum; fatty liver disease; lipid scramblase; lipoprotein metabolism.

Figures
Products