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In mice, deficiency in the high-density lipoprotein gene T39 stabilizes liver X receptor (LXR), reducing both atherosclerosis and steatohepatitis, suggesting that T39 inhibition could be an effective strategy for reducing these diseases. Anti-atherosclerosic and anti-steatohepatitic Genome-wide association studies have shown that single-nucleotide polymorphisms in the T39 gene, coding for the tetratricopeptide repeat protein 39B, are associated with increased high-density lipoprotein cholesterol levels. Here, Alan Tall and colleagues show in mice that T39 deficiency protects against atherosclerosis through a mechanism that involves stabilization of LXR, a known anti-atherogenic transcription factor. Unlike synthetic LXR ligands, however, T39 deficiency also protects against fatty liver, suggesting that T39 inhibition could be a therapeutic approach to both cardiovascular disease and non-alcoholic fatty liver disease. Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available 1 , are poorly understood. Despite the fact that its synthetic agonists induce fatty liver, the liver X receptor (LXR) transcription factor remains a target of interest because of its anti-atherogenic, cholesterol removal, and anti-inflammatory activities. Here we show that tetratricopeptide repeat domain protein 39B ( Ttc39b , C9orf52) ( T39 ), a high-density lipoprotein gene discovered in human genome-wide association studies 2 , promotes the ubiquitination and degradation of LXR. Chow-fed mice lacking T39 ( T39 −/− ) display increased high-density lipoprotein cholesterol levels associated with increased enterocyte ATP-binding cassette transporter A1 ( Abca1 ) expression and increased LXR protein without change in LXR messenger RNA. When challenged with a high fat/high cholesterol/bile salt diet, T39 −/− mice or mice with hepatocyte-specific T39 deficiency show increased hepatic LXR protein and target gene expression, and unexpectedly protection from steatohepatitis and death. Mice fed a Western-type diet and lacking low-density lipoprotein receptor ( Ldlr −/− T39 −/− ) show decreased fatty liver, increased high-density lipoprotein, decreased low-density lipoprotein, and reduced atherosclerosis. In addition to increasing hepatic Abcg5/8 expression and limiting dietary cholesterol absorption, T39 deficiency inhibits hepatic sterol regulatory element-binding protein 1 (SREBP-1, ADD1) processing. This is explained by an increase in microsomal phospholipids containing polyunsaturated fatty acids, linked to an LXRα-dependent increase in expression of enzymes mediating phosphatidylcholine biosynthesis and incorporation of polyunsaturated fatty acids into phospholipids. The preservation of endogenous LXR protein activates a beneficial profile of gene expression that promotes cholesterol removal and inhibits lipogenesis. T39 inhibition could be an effective strategy for reducing both steatohepatitis and atherosclerosis.

Background Functional gastrointestinal disorders present diagnostic and therapeutic challenges, and there is a strong need for molecular markers that enable early health insights and intervention. Herein, we present an approach to assess the gut microbiome with stool-based gut metatranscriptome data from a large adult human population ( n  = 80,570), using irritable bowel syndrome as an example that features both an abnormal gut microbiome and a spectrum of distinct conditions. Methods We develop a suite of eight gut microbial functional pathway scores, each of which represents the activity of a set of interacting microbial functional features (based on KEGG orthology) relevant to known gut biochemical activities. We use a normative approach within a subpopulation ( n  = 9,350) to define “Good” and ”Not Optimal” activities for these transcriptome-based gut pathway scores. Results We hypothesize that Not Optimal scores are associated with irritable bowel syndrome (IBS) and its subtypes (i.e., IBS-Constipation, IBS-Diarrhea, IBS-Mixed Type). We show that Not Optimal functional pathway scores are associated with higher odds of IBS or its subtypes within an independent cohort ( n  = 71,220) using both the Rome IV Diagnostic Questionnaire as well as self-reported phenotypes. Conclusions Rather than waiting to diagnose IBS after symptoms appear, these functional pathway scores can help to provide early health insights into molecular pathways that may contribute to IBS. These molecular endpoints could also assist with measuring the efficacy of practical interventions, developing related algorithms, providing personalized nutritional recommendations, diagnostic support, and treatments for gastrointestinal disorders like IBS.

Temporal regulation of nutrient and energy metabolism is emerging as an important aspect of metabolic homeostasis. The regulatory network that integrates the timing cues and nutritional signals to drive diurnal metabolic rhythms remains poorly defined. The 45-kDa isoform of ubiquitin-specific protease 2 (USP2-45) is a deubiquitinase that regulates hepatic gluconeogenesis and glucose metabolism. In this study, we found that USP2-45 is localized to peroxisomes in hepatocytes through a canonical peroxisome-targeting motif at its C-terminus. Clustering analysis indicates that the expression of a subset of peroxisomal genes exhibits robust diurnal rhythm in the liver. Despite this, nuclear hormone receptor PPARα, a known regulator of peroxisome gene expression, does not induce USP2-45 in hepatocytes and is dispensible for its expression during starvation. In contrast, a functional liver clock is required for the proper nutritional and circadian regulation of USP2-45 expression. At the molecular level, transcriptional coactivators PGC-1α and PGC-1β and repressor E4BP4 exert opposing effects on USP2-45 promoter activity. These studies provide insights into the subcellular localization and transcriptional regulation of a clock-controlled deubiquitinase that regulates glucose metabolism.

Hepatic gluconeogenesis is important for maintaining steady blood glucose levels during starvation and through light/dark cycles. The regulatory network that transduces hormonal and circadian signals serves to integrate these physiological cues and adjust glucose synthesis and secretion by the liver. In this study, we identified ubiquitin-specific protease 2 (USP2) as an inducible regulator of hepatic gluconeogenesis that responds to nutritional status and clock. Adenoviral-mediated expression of USP2 in the liver promotes hepatic glucose production and exacerbates glucose intolerance in diet-induced obese mice. In contrast, in vivo RNA interference (RNAi) knockdown of this factor improves systemic glycemic control. USP2 is a target gene of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a coactivator that integrates clock and energy metabolism, and is required for maintaining diurnal glucose homeostasis during restricted feeding. At the mechanistic level, USP2 regulates hepatic glucose metabolism through its induction of 11β-hydroxysteroid dehydrogenase 1 (HSD1) and glucocorticoid signaling in the liver. Pharmacological inhibition and liver-specific RNAi knockdown of HSD1 significantly impair the stimulation of hepatic gluconeogenesis by USP2. Together, these studies delineate a novel pathway that links hormonal and circadian signals to gluconeogenesis and glucose homeostasis.

It is increasingly recognized that an important step towards improving overall health is to accurately measure biomarkers of health from the molecular activities prevalent in the oral cavity. We present a general methodology for computationally quantifying the activity of microbial functional pathways using metatranscriptomic data. We describe their implementation as a collection of eight oral pathway scores using a large salivary sample dataset (n=9,350), and we evaluate score associations with oropharyngeal disease phenotypes within an unseen independent cohort (n=14,129). As clinical validation, we show that the relevant oral pathway scores are significantly worse in individuals with periodontal disease, acid reflux, and nicotine addiction, compared with controls. Given these associations, we make the case to use these oral pathway scores to provide molecular health insights from simple, non-invasive saliva samples, and as molecular endpoints for actionable interventions to address the associated conditions.Competing Interest StatementThe material represents original research, has not been previously published (is deposited as a preprint in biorxiv.org) and has not been submitted for publication elsewhere while under consideration in CSBJ. All authors of this manuscript were employees of Viome Life Sciences Inc at the time of their contributions, and held stock options in the company. MV and GB hold management positions within the company. The work was funded by Viome Life Sciences Inc.

Hepatic gluconeogenesis is important for maintaining steady blood glucose levels during starvation and through light/dark cycles. The regulatory network that transduces hormonal and circadian signals serves to integrate these physiological cues and adjust glucose synthesis and secretion by the liver. In this study, we identified ubiquitin-specific protease 2 (USP2) as an inducible regulator of hepatic gluconeogenesis that responds to nutritional status and clock. Adenoviral-mediated expression of USP2 in the liver promotes hepatic glucose production and exacerbates glucose intolerance in diet-induced obese mice. In contrast, in vivo RNA interference (RNAi) knockdown of this factor improves systemic glycemic control. USP2 is a target gene of peroxisome proliferator-activated receptor [gamma] coactivator-1[alpha] (PGC-1[alpha]), a coactivator that integrates clock and energy metabolism, and is required for maintaining diurnal glucose homeostasis during restricted feeding. At the mechanistic level, USP2 regulates hepatic glucose metabolism through its induction of 11[beta]-hydroxysteroid dehydrogenase 1 (HSD1) and glucocorticoid signaling in the liver. Pharmacological inhibition and liver-specific RNAi knockdown of HSD1 significantly impair the stimulation of hepatic gluconeogenesis by USP2. Together, these studies delineate a novel pathway that links hormonal and circadian signals to gluconeogenesis and glucose homeostasis. Diabetes 61: 1025-1035, 2012

Hepatic gluconeogenesis is important for maintaining steady blood glucose levels during starvation and through light/dark cycles. The regulatory network that transduces hormonal and circadian signals serves to integrate these physiological cues and adjust glucose synthesis and secretion by the liver. In this study, we identified ubiquitin-specific protease 2 (USP2) as an inducible regulator of hepatic gluconeogenesis that responds to nutritional status and clock. Adenoviral-mediated expression of USP2 in the liver promotes hepatic glucose production, whereas RNAi knockdown of this factor results in hypoglycemia due to impaired hepatic gluconeogenesis. USP2 is required for maintaining diurnal glucose homeostasis during restricted feeding. Elevated hepatic gluconeogenesis exacerbates the development of hyperglycemia in diabetes. In vivo gain- and loss-of-function studies indicate that USP2 regulates systemic glucose metabolism in insulin resistant state through modulation of hepatic glucocorticoid signaling and the gluconeogenic program. Together, these studies delineate a novel pathway that links hormonal and clock signaling to hepatic gluconeogenesis and glucose homeostasis.

We describe a data-driven computational approach for quantifying the microbial functional pathways in the gastrointestinal tract, based on an analysis of stool metatranscriptomic data within a large and diverse adult human population (n = 66,545). We develop a suite of eight gut microbial pathway scores, each of which represents the activity of a well-defined set of microbial functional features relevant to known gut biochemical activities. We use a normative approach within a subpopulation (n = 9,350) to determine the optimal and non-optimal levels of activity of these functional pathway scores. We hypothesize that non-optimal scores are associated with irritable bowel syndrome (IBS) and its subtypes (i.e., IBS-Constipation, IBS-Diarrhea, IBS-Mixed Type). We show that non-optimal scores within these microbial functional pathways are associated with higher odds of IBS or its subtypes within an independent cohort (n = 57,195). Given these findings, these gut pathway scores can be used to deliver meaningful health insights from simple, non-invasive stool samples, as potential molecular endpoints to measure the efficacy of practical interventions, and develop data-driven personalized algorithms aimed at providing nutritional recommendations, diagnostics, and treatments for IBS as well as related conditions.Competing Interest StatementAll authors are stockholders and either employees or paid advisors of Viome Inc, a commercial for-profit company

Functional gastrointestinal disorders present diagnostic and therapeutic challenges, and there is a strong need for molecular markers that enable early detection and intervention. Herein, we present an approach to assess an abnormal gut microbiome associated with irritable bowel syndrome using stool-based gut metatranscriptome data from a large adult human population (n = 80,570). We develop a suite of eight gut microbial functional pathway scores, each of which represents the activity of a set of interacting microbial functional features (based on KEGG orthology) relevant to known gut biochemical activities. We use a normative approach within a subpopulation (n = 9,350) to define “Good” and “Not Optimal” activities for these functional pathway scores. We hypothesize that Not Optimal scores are associated with irritable bowel syndrome (IBS) and its subtypes (i.e., IBS-Constipation, IBS-Diarrhea, IBS-Mixed Type). We show that Not Optimal functional pathway scores are associated with higher odds of IBS or its subtypes within an independent cohort (n = 71,220) using both the Rome IV Diagnostic Questionnaire as well as self-reported phenotypes. Rather than waiting to diagnose IBS after symptoms appear, these functional scores can help to provide early health insights into molecular pathways that may lead to IBS. These molecular endpoints could also assist with measuring the efficacy of practical interventions, developing related algorithms, providing personalized nutritional recommendations, diagnostics, and treatments for gastrointestinal disorders like IBS.