TMEM41B acts as an ER scramblase required for lipoprotein biogenesis and lipid homeostasis.
Cell Metab
; 33(8): 1655-1670.e8, 2021 08 03.
Article
in English
| MEDLINE | ID: covidwho-1233395
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
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Phospholipids
/
Endoplasmic Reticulum
Limits:
Animals
Language:
English
Journal:
Cell Metab
Journal subject:
Metabolism
Year:
2021
Document Type:
Article
Affiliation country:
J.cmet.2021.05.006
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