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The role of HMG-coenzyme A reductase (HMGCR) and statin medication in the Central Nervous System: Cognitive Functions, Metabolism, Feeding and Sleep Behaviour
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. (Uppsala University, Department of Neuroscience, Functional Pharmacology Unit)
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Millions of people are currently on statin medications (HMGCR inhibitors) to prevent cardiovascular diseases. Despite considerable central nervous system expression, little is known about HMGCR function in the brain. In Paper I, we used Drosophila and rodent models and found that inhibiting Hmgcr expression in the insulin-producing cells of the Drosophila hypothalamus equivalent, known as the pars intercerebralis (PI), throughout development, significantly reduces the expression of Insulin–like peptides 2 and 3 (ILP2 and ILP3), severely decreasing insulin signalling. This reduction causes decreased body size, hyperglycemia, increased lipid storage, and hyperphagia. We also discovered that Farnesyl pyrophosphate synthase (Fpps), an enzyme downstream of Hmgcr in the mevalonate pathway, is required for ILP2 expression in the PI. In rodents, acute inhibition of hypothalamic Hmgcr stimulates food intake as well. Furthermore, in rats, we found two regions within the hypothalamus that had significantly increased neural activity, the paraventricular nucleus and arcuate nucleus, which are known to regulate food intake. In Paper II, we explored the effects of statins on cognition and performed an observational study on a population-based sample from the UK Biobank. Cognitive performance in terms of reaction time, working memory and fluid intelligence was analysed at baseline and two follow-ups. Subjects were classified depending on age (up to 65 and over 65 years). The effect of statin use differed between the two age groups, with a beneficial effect on reaction time in older persons and fluid intelligence in both age groups, and a negative effect on working memory in younger subjects. In Paper III, we examined association of single nucleotide polymorphisms within the HMGCR gene, rs17238484 and rs12916, with self-reported insomnia symptoms. We found that statin users are associated with a higher risk for self-reported insomnia. The HMGCR genetic variants were also associated with self-reported insomnia, but in different manner. Carriers the rs12916-T risk allele had a protective effect from insomnia symptoms. No associations were found for either statin takers or carriers of these HGCMR risk alleles and late evening chronotype. The increased risk of insomnia noted with statins is partially explained by a mechanism that might be independent of HMGCR inhibition. In Paper IV, we discovered a novel role for Hmgcr in sleep regulation in Drosophila, where lacking of pan-neuronal Hmgcr expression causes sleep-promoting effects. We also found that loss of Hmgcr expression specifically in the PI insulin-producing cells, recapitulates the effect of pan-neuronal Hmgcr inhibition. Conversely, inhibiting Hmgcr in only six PI DH44 expressing neurons has the opposite effect on sleep, increasing sleep latency and decreasing sleep duration. This bi-functional property of Hmgcr in the fly brain underlies its importance in sleep regulation. Furthermore, loss of Hmgcr showed no effect on circadian rhythm, suggesting that Hmgcr regulates sleep by pathways distinct from the circadian clock.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2021. , p. 35
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1739
Keywords [en]
Statin, cardiovascular disease, HMGCR, PCSK9, sleep, insomnia, circadian, Chronotype, feeding
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-439049ISBN: 978-91-513-1177-7 (print)OAI: oai:DiVA.org:uu-439049DiVA, id: diva2:1540621
Public defence
2021-05-20, A2:208b, BMC, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2021-04-29 Created: 2021-03-29 Last updated: 2021-05-25
List of papers
1. The statin target Hmgcr regulates energy metabolism and food intake through central mechanisms in Drosophila
Open this publication in new window or tab >>The statin target Hmgcr regulates energy metabolism and food intake through central mechanisms in Drosophila
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(English)Manuscript (preprint) (Other academic)
Keywords
Body maintenance index, Obesity, Statins, Metabolism, Feeding behavior
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-439044 (URN)
Available from: 2021-03-29 Created: 2021-03-29 Last updated: 2021-03-29
2. The Cognitive Effects of Statins are Modified by Age
Open this publication in new window or tab >>The Cognitive Effects of Statins are Modified by Age
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2020 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 6187Article in journal (Refereed) Published
Abstract [en]

To reveal new insights into statin cognitive effects, we performed an observational study on a population-based sample of 245,731 control and 55,114 statin-taking individuals from the UK Biobank. Cognitive performance in terms of reaction time, working memory and fluid intelligence was analysed at baseline and two follow-ups (within 5-10 years). Subjects were classified depending on age (up to 65 and over 65 years) and treatment duration (1-4 years, 5-10 years and over 10 years). Data were adjusted for health- and cognition-related covariates. Subjects generally improved in test performance with repeated assessment and middle-aged persons performed better than older persons. The effect of statin use differed considerably between the two age groups, with a beneficial effect on reaction time in older persons and fluid intelligence in both age groups, and a negative effect on working memory in younger subjects. Our analysis suggests a modulatory impact of age on the cognitive side effects of statins, revealing a possible reason for profoundly inconsistent findings on statin-related cognitive effects in the literature. The study highlights the importance of characterising modifiers of statin effects to improve knowledge and shape guidelines for clinicians when prescribing statins and evaluating their side effects in patients.

Place, publisher, year, edition, pages
Springer Nature, 2020
National Category
Gerontology, specialising in Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-421080 (URN)10.1038/s41598-020-63035-2 (DOI)000559946700020 ()32277109 (PubMedID)
Funder
Swedish Research Council
Available from: 2020-10-07 Created: 2020-10-07 Last updated: 2022-09-15Bibliographically approved
3. Differential associations of statin treatment and polymorphism in genes coding for HMGCR and PCSK9 to risk for insomnia
Open this publication in new window or tab >>Differential associations of statin treatment and polymorphism in genes coding for HMGCR and PCSK9 to risk for insomnia
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2021 (English)In: Frontiers in Bioscience-Landmark, Vol. 26, no 12, p. 1453-1463Article in journal (Refereed) Published
Abstract [en]

Importance: Statins have been linked to an increased risk for insomnia, but the literature is controversial. Moreover, it is unknown, if the potential effects are directly related to the inhibition of the statin target HMGCR, the subsequently lowered cholesterol levels, or other off-target effects of statins. Aims: To investigate the association of statin treatment and genetic proxies of cholesterol lowering drugs with the risk for insomnia and chronotype in a large population-based cohort. Methods: A cross-sectional cohort study based on baseline data collected between 2006–2010 in UK biobank cohort was conducted. European participants without any history of psychiatric/neurological disorders or of stroke and with available genetic data as well as information on statin use were included in the present study. Self-reported measures of insomnia and chronotype were analysed (a) in statin users versus control subjects, (b) subjects carrying single nucleotide polymorphisms (SNPs) in the HMGCR gene, which are associated with reduced enzymatic function and lower cholesterol levels (rs17238484 and rs12916) and (c) subjects carrying a SNP in the PCSK9 gene (rs1159147), which leads to lower cholesterol levels independent of HMGCR. The main analysis were performed using multivariable regression models. Statin treatment and SNPs in HMGCR and PCSK9 genes were used as exposures and main outcomes were insomnia and chronotype. Results: A total of 206,801participants (mean [SD] age, 57.5 [7.9] years; 56% women; 20% statin users) were included in the present study. Statin users had an increased risk of insomnia compared to controls (odds ratio [95% CI], 1.07 [1.03 to 1.11]; p = 1.42 × 10−4). A similar effect was observed for PCSK9 rs11591147-T allele (1.07 [1.01–1.14]; 0.014), while the two gene variants of HMGCR were associated with a reduced risk for insomnia (rs17238484-G: 0.97 [0.95 to 0.99]; 0.014 and rs12916-T: 0.97 [0.96 to 0.99]; 0.002). In regard to chronotype, there was no effect of either statin treatment or HMGCR SNPs, but the PCSK9 rs11591147-T allele was associated with a higher evening preference (1.17 [1.06 to 1.29]; 0.001). Conclusion: Our data suggests that statin treatment can pose an increased risk for insomnia in in the European population. Interestingly, there was no agreement between the effects of statins and the effects of reduced HMGCR activity based on genetic variants, suggesting that the observed unfavourable effect of statins on sleep is conveyed through other targets. This further explains why the literature on statin effects on sleep is not conclusive. Finally our data encourage further investigations into the molecular processes linking statins, HMGCR and PCSK9 to sleep behaviour.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2021
Keywords
insomnia; cronotype; statin treatment; genetic variants
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-439045 (URN)10.52586/5039 (DOI)000742514300009 ()
Funder
Swedish Research Council
Available from: 2021-03-29 Created: 2021-03-29 Last updated: 2024-04-03Bibliographically approved
4. HMG-Coenzyme A Reductase (Hmgcr) regulates consolidation and homeostasis of sleep in Drosophila
Open this publication in new window or tab >>HMG-Coenzyme A Reductase (Hmgcr) regulates consolidation and homeostasis of sleep in Drosophila
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-439047 (URN)
Available from: 2021-03-29 Created: 2021-03-29 Last updated: 2021-03-29

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