Mevalonate Pyrophosphate Decarboxylase in Stroke-Prone Spontaneously Hypertensive Rat Is Reduced from the Age of Two Weeks.

Michihara, Akihiro; Sawamura, Makoto; Yamori, Yukio; Akasaki, Kenji; Tsuji, Hiroshi

doi:10.1248/bpb.24.1417

Cited by 10 publications

(14 citation statements)

References 16 publications

(15 reference statements)

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“…As for MVD, Michihara et al reported that the levels of its activity, amount, and gene expression were lower in SHRSP than in WKY rats. [10][11][12] In the present study, such strain difference in the gene expression level was also shown. However, judging from the lower expression levels our results showed for many of the genes for the other cholesterol biosynthetic enzymes in SHRSP, the expression level of the Mvd gene cannot necessarily define the lower serum T-CHO level in SHRSP.…”

Section: Discussionsupporting

confidence: 69%

“…[9][10][11][12] The activity of HMGCR in SHRSP has been reported to be higher than that in WKY rats. 9) DNA microarray analysis in our present study showed that the level of Hmgcr gene expression in SHRSP was about 1.5-times higher than in WKY rats, while in real-time RT-PCR analysis no such significant difference could be shown.…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11][12] Since HMGCR activity was higher in SHRSP than in WKY rats, 9) HMGCR is hardly thought to be a cause of the lower serum T-CHO level in SHRSP. On the other hand, the expression and activity levels of MVD were lower in SHRSP, [10][11][12] suggesting that MVD might be a cause of the lower serum T-CHO level.To further understand the difference between SRHSP and WKY rats maintained on a standard diet in serum T-CHO, we comparatively examined the expression levels of the genes responsible for the biosynthesis of cholesterol together with that of the gene of sterol regulatory element-binding protein-2 (SREBP-2), a common transcription factor of the cholesterol biosynthetic enzyme genes. 13,14) The results obtained herein indicated that the expression levels of most of the genes tested were significantly lower in SHRSP than in WKY rats.…”

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Comparison of Constitutive Gene Expression Levels of Hepatic Cholesterol Biosynthetic Enzymes between Wistar-Kyoto and Stroke-Prone Spontaneously Hypertensive Rats

Nemoto

Ikeda

Ito

et al. 2013

Biological & Pharmaceutical Bulletin

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Serum total cholesterol amounts in the stroke-prone hypertensive rat (SHRSP) strain are lower than in the normotensive control strain, Wistar-Kyoto (WKY) rat. To understand the strain difference, constitutive gene expression levels of hepatic cholesterol biosynthetic enzymes in male 8-week-old SHRSP and WKY rats were comparatively examined by DNA microarray and real-time reverse transcription-polymerase chain reaction (RT-PCR) analyses. Of 22 cholesterol biosynthetic enzyme genes, expression levels of 8 genes, Pmvk, Idi1, Fdps, Fdft1, Sqle, Lss, Sc4mol, and Hsd17b7, in SHRSP were less than 50% those of the WKY rats; especially, the expression level of Sqle gene, encoding squalene epoxidase, a rate-limiting enzyme in cholesterol biosynthesis pathway, was about 20%. The gene expression level of sterol regulatory element-binding protein-2 (SREBP-2), which functions as a transcription factor upregulating gene expression of cholesterol biosynthetic enzymes, in SHRSP was about 70% of that in WKY rats. These results demonstrate the possibility that the lower serum total cholesterol level in SHRSP is defined by lower gene expression of most hepatic cholesterol biosynthetic enzymes. In particular, decreased gene expression level of Sqle gene might be the most essential factor. Moreover, the broad range of lowered rates of these genes in SHRSP suggests that the abnormal function and/or expression not only of SREBP-2 but also of one or more other transcription factors for those gene expressions exist in SHRSP.Key words cholesterol biosynthesis; stroke-prone hypertensive rat; Wistar-Kyoto rat; strain difference; sterol regulatory element-binding protein-2; gene expression Stroke-prone spontaneously hypertensive rats (SHRSP) are widely used as a genetic model animal for hypertension and stroke.1,2) This strain also shows significantly lower serum total cholesterol (T-CHO) than the normotensive control strain, Wistar-Kyoto (WKY) rats, when both strains are maintained on a standard diet.3-5) However, the high-fat and highcholesterol diet-mediated development of hypercholesterolemia occurs more efficiently in SHRSP than in WKY rats.6-8) These findings suggest that there are differences in genetic factors responsible for cholesterol homeostasis.Serum T-CHO amount is primarily regulated by cholesterol biosynthesis, metabolism of cholesterol to bile acids, and uptake of cholesterol into cells via low-density lipoprotein (LDL) receptor in the liver. It is therefore one of important subjects for understanding the mechanism of strain difference between SHRSP and WKY strains, maintained on a standard diet, in serum T-CHO amount to look into strain differences in the expression and/or function of hepatic enzymes involved in cholesterol biosynthesis (Fig. 1). As for such differences, only two enzymes, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and mevalonate pyrophosphate decarboxylase (MVD), have been reported. [9][10][11][12] Since HMGCR activity was higher in SHRSP than in WKY rats, 9) HMGCR is hardly thought to be a cause of t...

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Comparison of Constitutive Gene Expression Levels of Hepatic Cholesterol Biosynthetic Enzymes between Wistar-Kyoto and Stroke-Prone Spontaneously Hypertensive Rats

Nemoto

Ikeda

Ito

et al. 2013

Biological & Pharmaceutical Bulletin

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“…47) Therefore, reductions in MPD hnRNA levels in the livers of SHRSP in the present study may have occurred from 2 weeks of age. We also hypothesized that the lower MPD hnRNA levels detected in the livers of SHRSP may have been caused by an increase in repressor binding to the silencer element in the promoter sequence of MPD or a decrease in activator binding to the enhancer element in the promoter region of MPD from 2 weeks of age if the reduction in MPD hnRNA levels that occurred due to changes in transcriptional factors was considered.…”

Section: Nm_022389mentioning

confidence: 66%

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

Michihara

Ide

Mizutani

et al. 2015

Bioscience, Biotechnology, and Biochemistry

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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.

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System‐wide analysis of hepatotoxicological responses: Tissomics is key

Kriete

Boyce²,

Love³

2006

Cytometry Pt A

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Background: Combining diverse data streams across different levels of biological observation, such as molecular, cellular, and clinical chemistry responses, support a system-wide diagnostic approach. Recent progress in slidebased cytometry contributes to the development of tissomics, a high-throughput and high-content phenotyping methodology that provides data-rich profiles of cellular heterogeneity in tissues enabling correlative statistical treatments over multiple scales of biological hierarchies. Methods: Phenotypical data are covariants that can be used as biomarkers to identify relevant candidate genes by associating initiating molecular events with phenotypical changes and adverse outcomes. We introduce a procedure of combined statistical and analytical tools to identify and visualize such associations for nonpooled entities. The new utility is applied to a time-controlled, low-dose toxi-

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Mevalonate Pyrophosphate Decarboxylase in Stroke-Prone Spontaneously Hypertensive Rat Is Reduced from the Age of Two Weeks.

Cited by 10 publications

References 16 publications

Comparison of Constitutive Gene Expression Levels of Hepatic Cholesterol Biosynthetic Enzymes between Wistar-Kyoto and Stroke-Prone Spontaneously Hypertensive Rats

Comparison of Constitutive Gene Expression Levels of Hepatic Cholesterol Biosynthetic Enzymes between Wistar-Kyoto and Stroke-Prone Spontaneously Hypertensive Rats

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

System‐wide analysis of hepatotoxicological responses: Tissomics is key

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