The role of HMG-coenzyme A reductase (HMGCR) and statin medication in the Central Nervous System : Cognitive Functions, Metabolism, Feeding and Sleep Behaviour

• 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.

Nyckelord

Statin

cardiovascular disease

HMGCR

PCSK9

sleep

insomnia

circadian

Chronotype

feeding

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