Phosphorylation of the liver X receptors

AbstractThe liver X receptors (LXRs) function as nutritional sensors for cholesterol and have important roles in lipid metabolism, glucose homeostasis, and inflammation. We provide the first evidence that LXRs are phosphorylated proteins. Mutational analysis and metabolic labeling indicate LXRα is phosphorylated on serine 198 in the hinge region. This is a consensus target for the MAPK family. A phosphorylation-deficient mutant, LXRα S198A, remains nuclear and responds to ligands like the wild-type protein. The biological significance of LXR phosphorylation remains to be elucidated but could provide a novel mechanism for the regulation of LXR signaling pathways and cellular metabolism

The Number of X Chromosomes Causes Sex Differences in Adiposity in Mice

Sexual dimorphism in body weight, fat distribution, and metabolic disease has been attributed largely to differential effects of male and female gonadal hormones. Here, we report that the number of X chromosomes within cells also contributes to these sex differences. We employed a unique mouse model, known as the “four core genotypes,” to distinguish between effects of gonadal sex (testes or ovaries) and sex chromosomes (XX or XY). With this model, we produced gonadal male and female mice carrying XX or XY sex chromosome complements. Mice were gonadectomized to remove the acute effects of gonadal hormones and to uncover effects of sex chromosome complement on obesity. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had up to 2-fold increased adiposity and greater food intake during daylight hours, when mice are normally inactive. Mice with two X chromosomes also had accelerated weight gain on a high fat diet and developed fatty liver and elevated lipid and insulin levels. Further genetic studies with mice carrying XO and XXY chromosome complements revealed that the differences between XX and XY mice are attributable to dosage of the X chromosome, rather than effects of the Y chromosome. A subset of genes that escape X chromosome inactivation exhibited higher expression levels in adipose tissue and liver of XX compared to XY mice, and may contribute to the sex differences in obesity. Overall, our study is the first to identify sex chromosome complement, a factor distinguishing all male and female cells, as a cause of sex differences in obesity and metabolism

Reactivation of Hepatitis B Virus: A Review of Clinical Guidelines

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The number of x chromosomes causes sex differences in adiposity in mice.

Sexual dimorphism in body weight, fat distribution, and metabolic disease has been attributed largely to differential effects of male and female gonadal hormones. Here, we report that the number of X chromosomes within cells also contributes to these sex differences. We employed a unique mouse model, known as the "four core genotypes," to distinguish between effects of gonadal sex (testes or ovaries) and sex chromosomes (XX or XY). With this model, we produced gonadal male and female mice carrying XX or XY sex chromosome complements. Mice were gonadectomized to remove the acute effects of gonadal hormones and to uncover effects of sex chromosome complement on obesity. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had up to 2-fold increased adiposity and greater food intake during daylight hours, when mice are normally inactive. Mice with two X chromosomes also had accelerated weight gain on a high fat diet and developed fatty liver and elevated lipid and insulin levels. Further genetic studies with mice carrying XO and XXY chromosome complements revealed that the differences between XX and XY mice are attributable to dosage of the X chromosome, rather than effects of the Y chromosome. A subset of genes that escape X chromosome inactivation exhibited higher expression levels in adipose tissue and liver of XX compared to XY mice, and may contribute to the sex differences in obesity. Overall, our study is the first to identify sex chromosome complement, a factor distinguishing all male and female cells, as a cause of sex differences in obesity and metabolism

Predictive Modeling of Colonoscopic Findings in a Fecal Immunochemical Test-Based Colorectal Cancer Screening Program.

BackgroundThe fecal immunochemical test (FIT) is the primary modality used by the Los Angeles County Department of Health Services (LADHS) for colorectal cancer (CRC) screening in average-risk patients. Some patients referred for FIT-positive diagnostic colonoscopy have neither adenomas nor more advanced pathology. We aimed to identify predictors of false-positive FIT (FP-FIT) results in our largely disenfranchised, low socioeconomic status population.MethodsWe conducted a retrospective study of 596 patients who underwent diagnostic colonoscopy following a positive screening FIT. Colonoscopies showing adenomas (or more advanced pathology) were considered positive. We employed multiple logistic and linear regression as well as machine learning models (MLMs) to identify clinical predictors of FP-FIT (primary outcome) and the presence of advanced adenomas (secondary outcome).ResultsOverall, 268 patients (45.0%) had a FP-FIT. Female sex and hemorrhoids (odds ratios [ORs] 1.59 and 1.89, respectively) were associated with increased odds of FP-FIT and fewer advanced adenomas (β = - 0.658 and  - 0.516, respectively). Conversely, increasing age and BMI (ORs 0.94 and 0.96, respectively) were associated with decreased odds of FP-FIT and a greater number of advanced adenomas (β = 0.073 and 0.041, respectively). MLMs predicted FP-FIT with high specificity (93.8%) and presence of advanced adenoma with high sensitivity (94.4%).ConclusionIncreasing age and BMI are associated with lower odds of FP-FIT and greater number of advanced adenomas, while female sex and hemorrhoids are associated with higher odds of FP-FIT and fewer advanced adenomas. The presence of the aforementioned predictors may inform the decision to proceed with diagnostic colonoscopy in FIT-positive patients

Differential gene expression in liver and fat tissues of X chromosome genes that escape inactivation.

<p>Genes previously shown to escape X chromosome inactivation (see text) were assessed for expression levels by quantitative PCR in liver and adipose tissue (subcutaneous inguinal and gonadal depots) of gonadectomized, chow fed FCG mice shown in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002709#pgen-1002709-g001" target="_blank">Figure 1B</a> (10 months post-GDX). (A) Statistical differences in gene expression levels among the FCG genotypes for genes escaping X chromosome inactivation. For each gene, the p value for differences between XX and XY, and female (F) vs. male (M), are shown. Several escapees exhibit increased expression in liver and/or adipose tissues of XX compared to XY mice; a few genes also exhibit differences between levels in gonadal females and gonadal males. <i>Mid1</i> shows a unique pattern, with lower expression levels in XX compared to XY tissues. The full name for <i>Rik</i> is 2610029G23Rik. NS, not significantly different. (B–D) mRNA levels are shown for liver and gonadal fat tissue of FCG mice for <i>Eif2s3x</i>, <i>Kdm6a</i>, and <i>Ddx3x</i>. Values shown for all bars represent mean ± SEM for the number of each genotype indicated. **, p<0.01; ‡, p<0.000001.</p

Increased body weight and fat mass in XX versus XY mice on a chow diet.

<p>(A) Body weight of four core genotype (FCG) mice at day 21 and day 45, prior to gonadectomy (GDX), and at 10 months after GDX. F, gonadal female; M, gonadal male. Values represent the mean ± SEM for the number of animals indicated in each bar. Significant comparisons for sex chromosome complement and for gonadal sex are denoted by brackets. A significant interaction of sex chromosome complement and gonadal sex is denoted by “Int.”. The p values are as described at the end of the legend. (B) Body weight curve for FCG mice from the point of gonadectomy through 10 months following gonadectomy. Values represent mean ± SEM. Values are significantly different between mice with XX vs. XY genotypes beginning at week 7 following GDX and beyond that. (C) Body composition of mice in panel (B) determined by NMR in FCG mice at 10 months after GDX. (D) Fat pad mass in mice from panel (B) at 10 months following GDX expressed as absolute mass (grams) or relative to kidney weight, which is invariant among the genotypes. (E) Plasma leptin levels and leptin mRNA levels in inguinal adipose tissue. *, p<0.05; **, p<0.01; ***, p<0.001; †, p<0.0001; ‡, p<0.000001.</p

Diet-induced fatty liver and impaired glucose homeostasis are more pronounced in XX than XY mice.

<p>FCG mice were fed a high fat-high carbohydrate diet for 16 weeks. All values represent mean ± SEM. (A) XX mice had increased liver mass and hepatic triglyceride levels compared to XY mice. (B) Hematoxylin and eosin staining of liver sections shows hepatic lipid droplet accumulation in XX mice. In the lower panel, thin layer chromatography demonstrates increased triglyceride levels in liver of XX mice relative to XY mice. (C) Fasting glucose and insulin levels, and homeostatic model assessment (HOMA) were determined. XX mice had significantly higher insulin levels than XY mice. (D) Fasting plasma triglyceride (TG) and free fatty acid (FFA) levels were higher in gonadal males than in gonadal females. (E) Increased triglyceride accumulation in XX liver is associated with increased peroxisome proliferator-activated receptor γ (<i>Pparg</i>) and diacylglycerol acyltransferase 1 (<i>Dgat1</i>) mRNA levels. (F) Increased expression levels for fatty acid oxidation genes acyl CoA oxidase 1 (<i>Aox</i>1) and carnitine palmitoyltransferase 1α (<i>Cpt1a</i>) in liver of XX mice. (G) Increased expression of Aox1 in skeletal muscle of gonadal male mice. *, p<0.05; **, p<0.01; ***, p<0.001; †, p<0.0001.</p