Depletion of essential isoprenoids and ER stress induction following acute liver-specific deletion of HMG-CoA reductase

Marco De Giorgi, Kelsey E. Jarrett, Jason C. Burton, Alexandria M. Doerfler, Ayrea Hurley, Ang Li, Rachel H. Hsu, Mia Furgurson, Kalyani R. Patel, Jun Han, Christoph H. Borchers, William R. Lagor

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

HMG-CoA reductase (Hmgcr) is the rate-limiting enzyme in the mevalonate pathway and is inhibited by statins. In addition to cholesterol, Hmgcr activity is also required for synthesizing nonsterol isoprenoids, such as dolichol, ubiquinone, and farnesylated and geranylgeranylated proteins. Here, we investigated the effects of Hmgcr inhibition on nonsterol isoprenoids in the liver. We have generated new genetic models to acutely delete genes in the mevalonate pathway in the liver using AAV-mediated delivery of Cre-recombinase (AAV-Cre) or CRISPR/Cas9 (AAVCRISPR). The genetic deletion of Hmgcr by AAV-Cre resulted in extensive hepatocyte apoptosis and compensatory liver regeneration. At the biochemical level, we observed decreased levels of sterols and depletion of the nonsterol isoprenoids, dolichol and ubiquinone. At the cellular level, Hmgcr-null hepatocytes showed ER stress and impaired N-glycosylation. We further hypothesized that the depletion of dolichol, essential for N-glycosylation, could be responsible for ER stress. Using AAV-CRISPR, we somatically disrupted dehydrodolichyl diphosphate synthase subunit (Dhdds), encoding a branch point enzyme required for dolichol biosynthesis. Dhdds-null livers showed ER stress and impaired N-glycosylation, along with apoptosis and regeneration. Finally, the combined deletion of Hmgcr and Dhdds synergistically exacerbated hepatocyte ER stress. Our data show a critical role for mevalonate-derived dolichol in the liver and suggest that dolichol depletion is at least partially responsible for ER stress and apoptosis upon potent Hmgcr inhibition.

Original languageEnglish
Pages (from-to)1675-1686
Number of pages12
JournalJournal of Lipid Research
Volume61
Issue number12
DOIs
Publication statusPublished - Dec 2020

Keywords

  • 3-hydroxy-3-methylglutarylcoenzyme A
  • Adeno-associated virus
  • Animal models
  • Cholesterol synthesis and regulation
  • Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9
  • Dehydrodolichyl diphosphate synthase subunit
  • Dolichol
  • Endoplasmic reticulum
  • Liver

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