Involvement of microRNA214 and transcriptional regulation in reductions in mevalonate pyrophosphate decarboxylase mRNA levels in stroke-prone spontaneously hypertensive rat livers

Abstract

Hypocholesterolemia has been epidemiologically identified as one of the causes of stroke (cerebral hemorrhage). We previously reported that lower protein levels of mevalonate pyrophosphate decarboxylase (MPD), which is responsible for reducing serum cholesterol levels in stroke-prone spontaneously hypertensive rats (SHRSP), in the liver were caused by a reduction in mRNA levels. However, the mechanism responsible for reducing MPD expression levels in the SHRSP liver remains unclear. Thus, we compared microRNA (miR)-214 combined with the 3′-untranslated region of MPD mRNA and heterogeneous nuclear RNA (hnRNA) between SHRSP and normotensive Wistar Kyoto rats (WKY). miR-214 levels in the liver were markedly higher in SHRSP than in WKY, whereas hnRNA levels were significantly lower. These results indicate that the upregulation of miR-214 and downregulation of MPD transcription in the liver both play a role in the development of hypocholesterolemia in SHRSP.

Lower Squalene Epoxidase and Higher Scavenger Receptor Class B Type 1 Protein Levels Are Involved in Reduced Serum Cholesterol Levels in Stroke-Prone Spontaneously Hypertensive Rats

“…22) Similar results (results of serum total cholesterol, HDL-, or VLDL/LDL-cholesterol) were obtained between WKY and SHRSP in the present study (data not shown). In order to identify the causes of these reductions in serum cholesterol and cholesterol content in the livers of SHRSP, the mRNA levels of LDLR, SRB1, and Abca1 were Fig.…”

“…21) Furthermore, we found that reductions in MPD expression levels in the livers of SHRSP were suggested to be controlled by the upregulation of microRNA (miR)-214 and downregulation of transcriptional levels. 22) miR was shown to reduce protein levels by inhibiting its synthesis from mRNA or accelerating the degradation of mRNA. 23,24) Recently, it was reported that phosphomevalonate kinase (PMVK), isopentenyl pyrophosphate isomerase (IPI), farnesyl pyrophosphate synthase (FPS), squalene synthase (SQS), squalene epoxidase (SQE), lanosterol synthase (LSS), methylsterol monooxygenase (Sc4mol) and hydroxysteroid (17β) dehydrogenase 7 (Hsd17b7) in the liver of SHRSP were significantly less than 50% those in WKY, when the mRNA levels of 22 cholesterol biosynthetic enzymes measured by real-time polymerase chain reaction (PCR).…”

“…23,24) A large number of miR were previously detected when miR combined with the 3′-untranslated region of SQE was searched for using microRNA.org. 22) Twelve miR (21, 124, 133a, 133b, 200a, 200b, 200c, 205, 224, 377, 429, and 494) combined with the 3′-untranslated region of SQE. The lower SQE mRNA levels in the livers of SHRSP may have been caused by an increase in miR combined with the 3′-untranslated region of SQE if the reduction in SQE mRNA levels plays a role in miR.…”

Stroke‐prone spontaneously hypertensive rats have reduced hydroxysteroid 17‐β dehydrogenase 7 levels for low cholesterol biosynthesis

“…We found that the hnRNA levels of HSD17B7 were significantly lower in SHRSP than in WKY, indicating that the reduced expression of HSD17B7 in SHRSP was indeed due to transcriptional regulation (Figure ). We had previously reported that the low levels of MPD were also caused by a decrease in transcription . Although sterol regulatory element‐binding proteins (SREBP) are well known transcriptional factors that inhibit cholesterol biosynthetic enzymes such as MPD and HSD17B7, no significant differences were observed in SREBP‐2 levels in the liver of SHRSP and WKY.…”

“…We have also previously shown that relative mRNA levels of IPI, SQS, LSS, sterol‐C5‐desaturase (SC5D), and 7‐dehydrocholesterol reductase (DHCR7) in the liver of SHRSP were the same as those in WKY . Further, the relative mRNA and protein levels of MPD and SQE were lower in the liver of SHRSP than in WKY . Anderson et al reported a correlation coefficiency of 0.48 between the abundance of mRNA and protein as determined by transcriptome and proteome analysis, suggesting that post‐transcriptional regulation of gene expression is a frequent phenomenon in higher organisms.…”