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Bassot A, Prip-Buus C, Alves A, et al. Loss and gain of function of Grp75 or mitofusin 2 distinctly alter cholesterol metabolism, but all promote triglyceride accumulation in hepatocytes. Biochim Biophys Acta Mol Cell Biol Lipids. 2021;1866(12):159030doi: 10.1016/j.bbalip.2021.159030.
Bassot, A., Prip-Buus, C., Alves, A., Berdeaux, O., Perrier, J., Lenoir, V., Ji-Cao, J., Berger, M. A., Loizon, E., Cabaret, S., Panthu, B., Rieusset, J., & Morio, B. (2021). Loss and gain of function of Grp75 or mitofusin 2 distinctly alter cholesterol metabolism, but all promote triglyceride accumulation in hepatocytes. Biochimica et biophysica acta. Molecular and cell biology of lipids, 1866(12), 159030. https://doi.org/10.1016/j.bbalip.2021.159030
Bassot, Arthur, et al. "Loss and gain of function of Grp75 or mitofusin 2 distinctly alter cholesterol metabolism, but all promote triglyceride accumulation in hepatocytes." Biochimica et biophysica acta. Molecular and cell biology of lipids vol. 1866,12 (2021): 159030. doi: https://doi.org/10.1016/j.bbalip.2021.159030
Bassot A, Prip-Buus C, Alves A, Berdeaux O, Perrier J, Lenoir V, Ji-Cao J, Berger MA, Loizon E, Cabaret S, Panthu B, Rieusset J, Morio B. Loss and gain of function of Grp75 or mitofusin 2 distinctly alter cholesterol metabolism, but all promote triglyceride accumulation in hepatocytes. Biochim Biophys Acta Mol Cell Biol Lipids. 2021 Dec;1866(12):159030. doi: 10.1016/j.bbalip.2021.159030. Epub 2021 Aug 20. PMID: 34419589.
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Biochim Biophys Acta Mol Cell Biol Lipids. 2021 Dec;1866(12):159030. doi: 10.1016/j.bbalip.2021.159030. Epub 2021 Aug 20.

Loss and gain of function of Grp75 or mitofusin 2 distinctly alter cholesterol metabolism, but all promote triglyceride accumulation in hepatocytes.

Biochimica et biophysica acta. Molecular and cell biology of lipids

Arthur Bassot, Carina Prip-Buus, Anaïs Alves, Olivier Berdeaux, Johan Perrier, Véronique Lenoir, Jingwei Ji-Cao, Marie-Agnès Berger, Emmanuelle Loizon, Stephanie Cabaret, Baptiste Panthu, Jennifer Rieusset, Béatrice Morio

Affiliations

  1. CarMeN Laboratory, INSERM U1060, INRAE U1397, Université Lyon 1, 69008 Lyon, France. Electronic address: [email protected].
  2. Institut Cochin, Département d'Endocrinologie, Métabolisme et Diabète, INSERM U1016/CNRS UMR8104/Université de Paris, 75014 Paris, France. Electronic address: [email protected].
  3. CarMeN Laboratory, INSERM U1060, INRAE U1397, Université Lyon 1, 69008 Lyon, France. Electronic address: [email protected].
  4. ChemoSens Platform, Centre des Sciences du Goût et de l'Alimentation, CNRS, INRA, Université Bourgogne Franche-Comté, Agrosup Dijon, F-21000 Dijon, France. Electronic address: [email protected].
  5. CarMeN Laboratory, INSERM U1060, INRAE U1397, Université Lyon 1, 69008 Lyon, France. Electronic address: [email protected].
  6. Institut Cochin, Département d'Endocrinologie, Métabolisme et Diabète, INSERM U1016/CNRS UMR8104/Université de Paris, 75014 Paris, France. Electronic address: [email protected].
  7. CarMeN Laboratory, INSERM U1060, INRAE U1397, Université Lyon 1, 69008 Lyon, France. Electronic address: [email protected].
  8. CarMeN Laboratory, INSERM U1060, INRAE U1397, Université Lyon 1, 69008 Lyon, France. Electronic address: [email protected].
  9. CarMeN Laboratory, INSERM U1060, INRAE U1397, Université Lyon 1, 69008 Lyon, France. Electronic address: [email protected].
  10. ChemoSens Platform, Centre des Sciences du Goût et de l'Alimentation, CNRS, INRA, Université Bourgogne Franche-Comté, Agrosup Dijon, F-21000 Dijon, France. Electronic address: [email protected].
  11. CarMeN Laboratory, INSERM U1060, INRAE U1397, Université Lyon 1, 69008 Lyon, France. Electronic address: [email protected].
  12. CarMeN Laboratory, INSERM U1060, INRAE U1397, Université Lyon 1, 69008 Lyon, France. Electronic address: [email protected].
  13. CarMeN Laboratory, INSERM U1060, INRAE U1397, Université Lyon 1, 69008 Lyon, France. Electronic address: [email protected].

PMID: 34419589 DOI: 10.1016/j.bbalip.2021.159030

Abstract

In the liver, contact sites between the endoplasmic reticulum (ER) and mitochondria (named MAMs) may be crucial hubs for the regulation of lipid metabolism, thus contributing to the exacerbation or prevention of fatty liver. We hypothesized that tether proteins located at MAMs could play a key role in preventing triglyceride accumulation in hepatocytes and nonalcoholic fatty liver disease (NAFLD) occurrence. To test this, we explored the role of two key partners in building MAM integrity and functionality, the glucose-regulated protein 75 (Grp75) and mitofusin 2 (Mfn2), which liver contents are altered in obesity and NAFLD. Grp75 or Mfn2 expression was either silenced using siRNA or overexpressed with adenoviruses in Huh7 cells. Silencing of Grp75 and Mfn2 resulted in decreased ER-mitochondria interactions, mitochondrial network fusion state and mitochondrial oxidative capacity, while overexpression of the two proteins induced mirror impacts on these parameters. Furthermore, Grp75 or Mfn2 silencing decreased cellular cholesterol content and enhanced triglyceride secretion in ApoB100 lipoproteins, while their overexpression led to reverse effects. Cellular phosphatidylcholine/phosphatidylethanolamine ratio was decreased only upon overexpression of the proteins, potentially contributing to altered ApoB100 assembly and secretion. Despite the opposite differences, both silencing and overexpression of Grp75 or Mfn2 induced triglyceride storage, although a fatty acid challenge was required to express the alteration upon protein silencing. Among the mechanisms potentially involved in this phenotype, ER stress was closely associated with altered triglyceride metabolism after Grp75 or Mfn2 overexpression, while blunted mitochondrial FA oxidation capacity may be the main defect causing triglyceride accumulation upon Grp75 or Mfn2 silencing. Further studies are required to decipher the link between modulation of Grp75 or Mfn2 expression, change in MAM integrity and alteration of cholesterol content of the cell. In conclusion, Grp75 or Mfn2 silencing and overexpression in Huh7 cells contribute to altering MAM integrity and cholesterol storage in opposite directions, but all promote triglyceride accumulation through distinct cellular pathways. This study also highlights that besides Mfn2, Grp75 could play a central role in hepatic lipid and cholesterol metabolism in obesity and NAFLD.

Copyright © 2021 Elsevier B.V. All rights reserved.

Keywords: Lipid homeostasis; Mitochondria-associated ER membranes; Non alcoholic fatty liver diseases

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