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

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.