Nuclear envelope–localized torsinA-LAP1 complex regulates hepatic VLDL secretion and steatosis
| Autor: | Cecilia Östlund, Chun Chi Liang, Sarah B. Gibeley, Antonio Hernandez-Ono, William T. Dauer, Michael Lee, Tatyana Fedotova, Ji Yeon Shin, Henry N. Ginsberg, Howard J. Worman |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Very low-density lipoprotein Nuclear Envelope Lipoproteins VLDL Mice 03 medical and health sciences 0302 clinical medicine Non-alcoholic Fatty Liver Disease Nonalcoholic fatty liver disease medicine Animals Inner membrane Secretion Mice Knockout Chemistry Membrane Proteins Lipid metabolism General Medicine Lipid Metabolism medicine.disease Cell biology 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Hepatocyte Hepatocytes Commentary Steatosis Steatohepatitis Carrier Proteins Molecular Chaperones |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | Deciphering novel pathways regulating liver lipid content has profound implications for understanding the pathophysiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Recent evidence suggests that the nuclear envelope is a site of regulation of lipid metabolism but there is limited appreciation of the responsible mechanisms and molecular components within this organelle. We showed that conditional hepatocyte deletion of the inner nuclear membrane protein lamina-associated polypeptide 1 (LAP1) caused defective VLDL secretion and steatosis, including intranuclear lipid accumulation. LAP1 binds to and activates torsinA, an AAA+ ATPase that resides in the perinuclear space and continuous main ER. Deletion of torsinA from mouse hepatocytes caused even greater reductions in VLDL secretion and profound steatosis. Both of these mutant mouse lines developed hepatic steatosis and subsequent steatohepatitis on a regular chow diet in the absence of whole-body insulin resistance or obesity. Our results establish an essential role for the nuclear envelope-localized torsinA-LAP1 complex in hepatic VLDL secretion and suggest that the torsinA pathway participates in the pathophysiology of nonalcoholic fatty liver disease. |
| Databáze: | OpenAIRE |
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