Dataset Information

The Statin Target HMG-Coenzyme a Reductase (Hmgcr) Regulates Sleep Homeostasis in Drosophila.

ABSTRACT: Statins, HMG Coenzyme A Reductase (HMGCR) inhibitors, are a first-line therapy, used to reduce hypercholesterolemia and the risk for cardiovascular events. While sleep disturbances are recognized as a side-effect of statin treatment, the impact of statins on sleep is under debate. Using Drosophila, we discovered a novel role for Hmgcr in sleep modulation. Loss of pan-neuronal Hmgcr expression affects fly sleep behavior, causing a decrease in sleep latency and an increase in sleep episode duration. We localized the pars intercerebralis (PI), equivalent to the mammalian hypothalamus, as the region within the fly brain requiring Hmgcr activity for proper sleep maintenance. Lack of Hmgcr expression in the PI insulin-producing cells recapitulates the sleep effects of pan-neuronal Hmgcr knockdown. Conversely, loss of Hmgcr in a different PI subpopulation, the corticotropin releasing factor (CRF) homologue-expressing neurons (DH44 neurons), increases sleep latency and decreases sleep duration. The requirement for Hmgcr activity in different neurons signifies its importance in sleep regulation. Interestingly, loss of Hmgcr in the PI does not affect circadian rhythm, suggesting that Hmgcr regulates sleep by pathways distinct from the circadian clock. Taken together, these findings suggest that Hmgcr activity in the PI is essential for proper sleep homeostasis in flies.

SUBMITTER: Alsehli AM

PROVIDER: S-EPMC8781969 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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The Statin Target HMG-Coenzyme a Reductase (Hmgcr) Regulates Sleep Homeostasis in <i>Drosophila</i>.

Alsehli Ahmed M AM Liao Sifang S Al-Sabri Mohamed H MH Vasionis Lukas L Purohit Archana A Behare Neha N Clemensson Laura E LE Williams Michael J MJ Schiöth Helgi B HB

Pharmaceuticals (Basel, Switzerland) 20220110 1

Statins, HMG Coenzyme A Reductase (HMGCR) inhibitors, are a first-line therapy, used to reduce hypercholesterolemia and the risk for cardiovascular events. While sleep disturbances are recognized as a side-effect of statin treatment, the impact of statins on sleep is under debate. Using Drosophila, we discovered a novel role for Hmgcr in sleep modulation. Loss of pan-neuronal <i>Hmgcr</i> expression affects fly sleep behavior, causing a decrease in sleep latency and an increase in sleep episode ...[more]

PMID: 35056136

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Project description:Statins are an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Growing evidence indicates that statins may have an anti-inflammatory effect. Whether genetically proxied HMGCR inhibition can reduce the risk of ankylosing spondylitis is unknown. We constructed an HMGCR genetic score comprising nearly randomly inherited variants significantly associated with LDL cholesterol levels within ± 100 kb from HMGCR to proxy for inhibition of HMGCR. We also constructed PCSK9 and NPC1L1 scores as well as the LDL polygenetic score to proxy for the inhibition of these drug targets as well as serum LDL cholesterol levels, respectively. We then compared the associations of these genetic scores with the risk of ankylosing spondylitis. Of 33,998 participants in the primary cohort, 12,596 individuals had been diagnosed with ankylosing spondylitis. Genetically proxied inhibition of HMGCR scaled to per mmol/L decrease in LDL cholesterol levels by the HMGCR score was associated with a lower risk of ankylosing spondylitis (OR, 0.57; 95% CI, 0.38-0.85; P value = 5.7 × 10-3). No significant association with ankylosing spondylitis was observed for the PCSK9 score (OR, 0.89; 95% CI, 0.68-1.16) and the NPC1L1 score (OR, 1.50; 95% CI, 0.39-5.77). For the LDL score, genetically determined per mmol/L decrease in LDL cholesterol levels led to a reduced risk of ankylosing spondylitis (OR, 0.64; 95% CI, 0.43-0.94), with significant heterogeneity and pleiotropy in the estimate. Exploratory analyses showed that genetically proxied inhibition of HMGCR appeared to have a similar effect to long-term statin therapy in modifying the risk of coronary artery disease and type 2 diabetes, suggesting that the HMGCR score might be a reliable model to assess the effect of statin. Genetically proxied inhibition of HMGCR was associated with a decreased risk of ankylosing spondylitis. This mechanism-based estimate was in line with existing observations suggesting the clinical benefits of statin therapy for ankylosing spondylitis.

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Dataset Information

The Statin Target HMG-Coenzyme a Reductase (Hmgcr) Regulates Sleep Homeostasis in Drosophila.

Publications

The Statin Target HMG-Coenzyme a Reductase (Hmgcr) Regulates Sleep Homeostasis in <i>Drosophila</i>.

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