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1.  Major risk factors for the appearance of white-matter lesions on MRI in hypertensive patients with controlled blood pressure 
Blood pressure (BP), age, and reduced renal function are major risk factors for white-matter lesions (WMLs) in the general population. However, it remains unclear whether or not the BP itself or other parameters related to the BP are associated with WMLs in hypertensive patients with well-controlled BP. We investigated the relationships of the presence of WMLs with the central systolic BP (cSBP) and estimated glomerular filtration rate (eGFR) in treated hypertensive patients.
We studied 185 hypertensive patients with median duration of hypertension, 10.0 years, whose BP is controlled to SBP and diastolic BP (DBP) of 139 ± 17 and 79 ± 10 mmHg, respectively. We measured cSBP and brain magnetic resonance imaging (MRI) was examined within 2 weeks after last BP and biological measurements.
Patients with higher-grade WMLs, as assessed by the presence of Scheltens deep white-matter hyperintensity (SDWMH) in the frontal (grade 0–2 vs 3–6) and parietal areas (grade 0–2 vs 3–6) where small arteries are affected at earlier stage of hypertension, as well as that of Fazekas deep white-matter hyperintensity (FDWMH) (grade 2–3 vs 0–1) and Fazekas periventricular hyperintensity (FPVH) (grade 1–3 vs 0) were older, had higher serum creatinine levels, a longer duration of hypertension, and lower eGFR values. The grade of the WMLs was not associated with either the cSBP or the brachial SBP. In logistic regression analyses after adjustment for age, sex, cSBP, and hypertension duration, showed significant association between eGFR and WMLs. The patients with lower eGFR (<60 mL/minute/1.73 m2) tended to have higher grade WMLs. The odds ratio was 2.87 for FDWMH (P = 0.017), 1.99 for FPVH (P = 0.131), and 2.33 for SDWMH in the parietal area (P = 0.045).
Presence of WMLs was associated with eGFR, but not with either the brachial SBP or cSBP in hypertensive patients with well-controlled BP.
PMCID: PMC3310357  PMID: 22454561
white-matter lesions; central systolic blood pressure; estimated glomerular filtration rate
2.  Hepatic steatosis in leptin-deficient mice is promoted by the PPARγ target gene, fat-specific protein 27 
Cell metabolism  2008;7(4):302-311.
PPARγ is induced in leptin-deficient mouse (ob/ob) liver and is critical for the development of hepatic steatosis. The present study shows that fsp27 in ob/ob liver is a direct target gene of PPARγ and can elevate hepatic triglyceride levels. Fsp27 belongs to the cide family, composed of cide a, cide b and fsp27/cide c, that all contain a conserved CIDE-N domain. Fsp27 was recently reported to be a lipid droplet-binding protein and to promote lipid accumulation in adipocytes. The fsp27 gene was expressed at high levels in ob/ob liver, and at markedly lower levels in ob/ob livers lacking PPARγ. Forced expression of fsp27 by adenovirus, in hepatocytes in vitro or in vivo, led to increased triglyceride levels. Knockdown by adenovirus expressing fsp27-shRNA resulted in lower accumulation of hepatic triglycerides compared to control adenovirus-infected liver. Taken together, these results indicate that the fsp27 is a direct mediator of PPARγ-dependent hepatic steatosis.
PMCID: PMC2587176  PMID: 18396136
PPAR; PPARgamma; fsp27; cide; triglyceride; knockout mouse; fatty liver; ob/ob
3.  Ligand-activated PPARβ efficiently represses the induction of LXR-dependent promoter activity through competition with RXR 
Angiopoietin-like protein 3 (angptl3), a member of the vascular endothelial growth factor family, was shown to play an important role in regulating lipid metabolism. To elucidate the mechanism by which PPARβ represses angptl3 promoter activity, reporter constructs were prepared and transfection analysis carried out. PPARβ repressed angptl3-Luc promoter activity and activation of PPARβ by L-165041, a PPARβ-specific ligand, increased the extent of repression. The repression by L-165041 was lost in angptl3-Luc plasmids having a deleted or mutated LXRα binding site (DR4). PPARβL405R, deficient in RXRα binding, had no effect on angptl3-Luc promoter activity. PPARβ did not repress the activity of GAL4-LXRα which activates of GAL4DBD TK-Luc independent of RXR. Addition of RXRα completely abolished the repression of angptl3-Luc activity by PPARβ. Mammalian two-hybrid analysis revealed that PPARβ ligand binding enhanced the dissociation of the LXRα-RXRα heterodimer. Gel shift assays also indicated that PPARβ ligand binding increased dissociation of LXRα/RXRα binding to a DR4 oligonucleotide probe; addition of RXRα restored the binding lost by addition of PPARβ. Collectively, these results suggest that the binding of PPARβ-specific ligand enhances the affinity between RXRα and activated PPARβ and thus may regulate angptl3 gene expression through a DR4 element by competing with LXRα for RXRα.
PMCID: PMC1544360  PMID: 16806672
PPAR; PPARβ/δ; Triglyceride; Angiopoietin; LXR; RXR; angptl3, mouse angiopoietin-like 3; LXR, liver X receptor; RXR, retinoid X receptor; PPAR, peroxisome proliferator-activated receptor; FXR, farnesoid-X-receptor; VLDL, very low density lipoprotein; HF, high fat
4.  A human RNA polymerase II subunit is encoded by a recently generated multigene family 
The sequences encoding the yeast RNA polymerase II (RPB) subunits are single copy genes.
While those characterized so far for the human (h) RPB are also unique, we show that hRPB subunit 11 (hRPB11) is encoded by a multigene family, mapping on chromosome 7 at loci p12, q11.23 and q22. We focused on two members of this family, hRPB11a and hRPB11b: the first encodes subunit hRPB11a, which represents the major RPB11 component of the mammalian RPB complex ; the second generates polypeptides hRPB11bα and hRPB11bβ through differential splicing of its transcript and shares homologies with components of the hPMS2L multigene family related to genes involved in mismatch-repair functions (MMR). Both hRPB11a and b genes are transcribed in all human tissues tested. Using an inter-species complementation assay, we show that only hRPB11bα is functional in yeast. In marked contrast, we found that the unique murine homolog of RPB11 gene maps on chromosome 5 (band G), and encodes a single polypeptide which is identical to subunit hRPB11a.
The type hRPB11b gene appears to result from recent genomic recombination events in the evolution of primates, involving sequence elements related to the MMR apparatus.
PMCID: PMC61041  PMID: 11747469
5.  Induction of Transformation and p53-Dependent Apoptosis by Adenovirus Type 5 E4orf6/7 cDNA 
Journal of Virology  1999;73(12):10095-10103.
Adenovirus (Ad) E4orf6/7, one of the early gene products of human Ads, forms a stable complex with the cellular transcription factor E2F to activate transcription from the Ad E2 promoter. E2F cDNAs have growth-promoting and apoptosis-inducing activities when overexpressed in cells. We cloned Ad5 E4orf6/7 cDNA in both simian virus 40- and human cytomegalovirus-based expression vectors to examine its transforming and apoptotic activities. The cloned E4orf6/7 collaborated with a retinoblastoma protein (RB)-nonbinding and therefore E2F-nonreleasing mutant of Ad5 E1A (dl922/947) to morphologically transform primary rat cells, suggesting that E2F is an important cellular protein functioning downstream of E1A for transformation. In a G418 colony formation assay, E4orf6/7 was shown to suppress growth of untransformed rat cells. Moreover, a recombinant Ad expressing Ad5 E4orf6/7 induced apoptosis in rat cells when coinfected with wild-type p53-expressing Ad. Mutational analysis of E4orf6/7 revealed that both of the domains required for growth inhibition and transformation by E4orf6/7 lay in the C-terminal region, which is essential for transactivation from the upstream sequence of an E2a promoter containing E2F-binding sites. However, the smallest mutant of E4orf6/7, encoding the C-terminal 59 amino acids, failed to complement the RB-nonbinding dl922/947 mutant despite showing growth inhibition and E2F transactivation activities. Thus, it is suggested that a subregion of E4orf6/7 which is required for growth inhibition and transformation in collaboration with dl922/947 overlaps the transactivation domain of E4orf6/7.
PMCID: PMC113061  PMID: 10559324

Results 1-5 (5)