Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase

Molecular and Cellular Biochemistry - Within the last few years considerable evidence has accumulated which indicates that changes in HMG-CoA reductase are due primarily, if not solely, to changes...     

Localization and quantification of the cytoskeleton-associated protein adducin in the kidneys of normal and Milan hypertensive rats

 Hypertension and kidney dysfunction in sodium transport observed in the Milan hypertensive strain (MHS) of rats are genetically associated with point mutations of adducin, an actin- and spectrin-binding protein of the membrane cytoskeleton. Polymorphism in the adducin locus has been reported to occur also in cases of human primary hypertension. In this study we show by immunostaining that adducin is localized along the basolateral epithelial membrane surface of the entire proximal and distal tubule with no detectable differences between MHS rats and the normotensive control strain (MNS). However, the total amount of adducin in kidney homogenates is reduced by about 45% in MHS rats as determined by quantitative immunoblotting. In erythrocyte membranes of MHS rats, adducin is reduced approximately 10%. The reduction of renal adducin in MHS rats is mainly caused by a reduction of the adducin pool that is loosely associated with kidney membranes and can be released by the non-ionic detergent, Triton X-100. The Triton-resistant, tightly membrane-bound pool of renal adducin differed by approximately 10% between MHS and MNS rats. Since several ion transporters have been shown to be tethered to the membrane cytoskeleton, we suppose that the reduction of the dynamic, loosely bound pool of adducin in MHS rats might interfere with the normal turnover and incorporation of yet unknown transporters involved in kidney sodium transport. However, the Na⁺,K⁺-ATPase appears to be not involved, as indicated by normal distribution and amounts of NA⁺,K⁺-ATPase in the kidney of MHS rats revealed by immunostaining and immunoblotting. Accepted: 23 June 1997     

Sedentary Behavior and Obesity in a Large Cohort of Children

The purpose of this study was to examine the association between sedentary behavior and obesity among 12‐year‐old children, while adjusting for moderate‐to‐vigorous physical activity (MVPA) and other potential confounding variables. Cross‐sectional analyses were carried out with data from 5,434 children who participated in the Avon Longitudinal Study of Parents and Children (ALSPAC). Fat mass was derived using dual‐energy X‐ray emission absorptiometry, and height and weight measurements were used to calculate BMI (kg/m²). The children wore an accelerometer for 7 days. The cut points for sedentary behavior and MVPA were ≤199 and ≥3,600 counts per minute (cpm), respectively. Logistic regression analyses were performed to estimate odds ratios (ORs), adjusting for potential confounders of physical activity that included gender, social factors, early life factors, and maturation. The minimally adjusted association between sedentary behavior and obesity was positive, OR = 1.18 (1.08, 1.28). After adjusting for the series of potential confounders of physical activity the positive association remained, OR = 1.32 (1.14, 1.53). The crude association between 15 min of MVPA per day and obesity was negative, OR = 0.54 (0.48, 0.62). When 15 min of MVPA per day was additionally controlled for in the models, the positive associations between sedentary behavior and obesity were negated. Sedentary behavior was positively associated with obesity in the 12‐year‐old children, but this association was not independent of MVPA; low levels of MVPA among the sedentary children increased the odds of obesity. These findings support the importance of specifically engaging in MVPA during childhood to reduce the prevalence of obesity.     

Plasma amyloid and tau as dementia biomarkers in Down syndrome: Systematic review and meta‐analyses

Individuals with Down syndrome (DS) are at high risk of developing Alzheimer's disease (AD). Discovering reliable biomarkers which could facilitate early AD diagnosis and be used to predict/monitor disease course would be extremely valuable. To examine if analytes in blood related to amyloid plaques may constitute such biomarkers, we conducted meta‐analyses of studies comparing plasma amyloid beta (Aβ) levels between DS individuals and controls, and between DS individuals with and without dementia. PubMed, Embase, and Google Scholar were searched for studies investigating the relationship between Aβ plasma concentrations and dementia in DS and 10 studies collectively comprising >1,600 adults, including >1,400 individuals with DS, were included. RevMan 5.3 was used to perform meta‐analyses. Meta‐analyses showed higher plasma Aβ₄₀ (SMD = 1.79, 95% CI [1.14, 2.44], Z = 5.40, p < .00001) and plasma Aβ₄₂ levels (SMD = 1.41, 95% CI [1.15, 1.68], Z = 10.46, p < .00001) in DS individuals than controls, and revealed that DS individuals with dementia had higher plasma Aβ₄₀ levels (SMD = 0.23, 95% CI [0.05, 0.41], Z = 2.54, p = .01) and lower Aβ₄₂/Aβ₄₀ ratios (SMD = ?0.33, 95% CI [?0.63, ?0.03], Z = 2.15, p = .03) than DS individuals without dementia. Our results indicate that plasma Aβ₄₀ levels may constitute a promising biomarker for predicting dementia status in individuals with DS. Further investigations using new ultra‐sensitive assays are required to obtain more reliable results and to investigate to what extent these results may be generalizable beyond the DS population.     

Sex and season predict wounds in zoo-housed Japanese macaques (Macaca fuscata): A multi-institutional study

Japanese macaque societies are characterized by frequent intragroup conflict both in free-ranging and zoo-housed conditions. In zoos, understanding the factors that contribute to wounding is of interest because this knowledge can aid in proactive husbandry and management planning that can minimize the negative impacts wounding can have on individual welfare. This study sought to determine whether the variables sex, season and age predicted wounding rates. Data were collected for 24 months on 119 Japanese macaques living in 10 zoos, and we analyzed the contribution of variables using generalized linear mixed models. A total of 1,007 wounds were reported, and the best model included the interaction between sex and season. Follow-up analyses revealed that females incurred more wounds than males, and this sex difference was more pronounced during the breeding compared to the nonbreeding season. On average, individuals received 4.67 (±SEM: 0.55) wounds per year and 77.31% of the population incurred at least one wound in the study period. The majority of wounds were superficial and did not require veterinary intervention. Wound locations were not randomly distributed across body regions and were most often reported on the face. Finally, macaques living in larger social groups experienced more wounds, on average. This study represents the first quantification of wounding in this species and may provide insight to help inform husbandry and management strategies in zoos.     

Regulation of hepatic beta-hydroxy-beta-methylglutaryl coenzyme A reductase by the interplay of hormones

We have previously established that insulin causes a marked and rapid stimulation of hepatic β-hydroxy-β-methylglutaryl coenzyme A reductase activity in normal and diabetic rats [Biochem. Biophys. Res. Commun.50, 504 (1973)], whereas l-triiodothyronine stimulates the reductase activity to supranormal levels in hypophysectomized rats two days after administration [Proc. Nat. Acad. Sci. (1974) In press]. In the present investigation it is demonstrated that the stimulation of the reductase activity in hypophysectomized-diabetic rats requires the mediation of both insulin and l-triiodothyronine. Neither hormone alone is effective. The rapid stimulation of reductase activity by insulin and the delayed stimulation elicited by l-triiodothyronine are both inhibited by either glucagon or hydrocortisone. Thus, an interplay of hormones regulates reductase activity and consequently cholesterol biosynthesis.     

AN EXAMINATION OF POLYPLOIDY AND PUTATIVE INTROGRESSION IN CALOCHORTUS SUBSECTION NUDI (LILIACEAE)

Calochortus subsection Nudi (section Calochortus) comprises four extant species distributed from central California to southern Oregon. To elucidate relationships within this group, morphological, cytological, and electrophoretic investigations were undertaken. Allozyme data revealed two distinct groups in subsection Nudi: a coastal group, comprising C. uniflorus and C. umbellatus; and a Sierran group, comprising C. minimus and C. nudus. Calochortus uniflorus consists of diploids (n = 10) and tetraploids (n = 20). Several lines of evidence suggest that tetraploid C. uniflorus may be an autotetraploid: 1) quadrivalents were observed during meiosis in tetraploid C. uniflorus; 2) the mean genetic identity between the diploid and tetraploid cytotypes was much higher (Ī = 0.963) than between either cytotype and C. umbellatus (Ī = 0.903 and 0.904 for 2x and 4x, respectively); 3) diploid and tetraploid individuals of C. uniflorus were indistinguishable morphologically; and 4) both cytotypes of C. uniflorus occupy vernal meadows, whereas C. umbellatus occupies exposed serpentine ridges. Data from morphology and enzyme electrophoresis suggest that introgression, or at least extensive hybridization, has occurred between C. minimus and C. nudus. Principal coordinate analysis showed that pure C. minimus and C. nudus are morphologically distinct and that putatively introgressive populations are morphologically intermediate. Most putatively introgressive populations displayed reduced pollen viability relative to pure C. minimus and C. nudus. Allozyme data are consistent with the concept that hybridization and possibly introgression may have occurred between C. minimus and C. nudus. When allozyme data were analyzed by the unweighted pair-group method of cluster analysis using arithmetic means, most putatively introgressive populations were placed between the C. minimus and C. nudus populations.     

Influence of mevalonate kinase on studies of the MgATP-dependent inactivator of 3-hydroxy-3-methylglutaryl coenzyme A reductase

The nature of the MgATP-dependent inactivator of 3-hydroxy-3-methylglutaryl coenzyme A reductase has been studied. Several observations suggest that reductase inactivator preparations from both microsomes and cytosol possess mevalonate kinase activity. (1) Reductase inactivator (reductase kinase) activity copurified with mevalonate kinase activity. (2) Inactivator activity was inhibited by geranyl pyrophosphate and farnesyl pyrophosphate, known to be potent inhibitors of mevalonate kinase. (3) Addition of an excess of mevalonate completely prevented inhibition of reductase activity. (4) Formation of phosphomevalonate fully accounted for the decreased amount of mevalonate formed in the presence of inactivator and MgATP. (5) When reductase activity was measured by NADPH oxidation, no inhibition was observed. Clearly, the presence of mevalonate kinase in reductase inactivator preparations can lead to misinterpretations concerning whether reductase activity is regulated by phosphorylation-dephosphorylation. In this paper, we present several methods and approaches which can be used to critically evaluate this possibility.     

Mouse kidney nonpolysomal messenger ribonucleic acid: metabolism, coding function, and translational activity

To elucidate the distribution and function of mRNA in mouse kidney cytoplasm, we compared mRNA isolated from polysomal (greater than 80S) and native postpolysomal (20--80S) ribonucleoproteins with respect to synthesis and lifetime, sequence content, and translational activity. The 20--25% of cytoplasmic mRNA recovered from postpolysomal ribonucleoprotein is similar to polysomal mRNA in size (20--22S), in apparent half-life (11--13 h), in major products of cell-free translation, and in nucleotide complexity (approximately 4 x 10(7) nucleotides). The labeling kinetics of polysomal and postpolysomal mRNA suggest these mRNA populations are in equilibrium. [3H]cDNAs transcribed from polysomal and from postpolysomal poly(A)-containing mRNAs react with template mRNA and with the heterologous mRNA at the same rate (Cot1/2 approximately 6.3 mol.s/L) and to the same extent (95%). Therefore, these mRNAs are equally diverse and homologous and occur at similar relative frequencies. Postpolysomal mRNA directs cell-free protein synthesis at only approximately 30% of the rate of polysomal mRNA and to only 30% of the extent of mRNA from polysomes. Postpolysomal mRNA is approximately 3-fold less sensitive than polysomal mRNA to inhibition of translation by m7GMP, suggesting postpolysomal mRNA contains a greater fraction of molecules deficient in 5'-terminal caps. Postpolysomal mRNA may derive from renal mRNAs that initiate translation inefficiently and thus accumulate as postpolysomal ribonucleoproteins.