Publications by authors named "Simon Hui"

25 Publications

  • Page 1 of 1

Genetic regulation of liver lipids in a mouse model of insulin resistance and hepatic steatosis.

Mol Syst Biol 2021 01;17(1):e9684

Division of Cardiology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.

To elucidate the contributions of specific lipid species to metabolic traits, we integrated global hepatic lipid data with other omics measures and genetic data from a cohort of about 100 diverse inbred strains of mice fed a high-fat/high-sucrose diet for 8 weeks. Association mapping, correlation, structure analyses, and network modeling revealed pathways and genes underlying these interactions. In particular, our studies lead to the identification of Ifi203 and Map2k6 as regulators of hepatic phosphatidylcholine homeostasis and triacylglycerol accumulation, respectively. Our analyses highlight mechanisms for how genetic variation in hepatic lipidome can be linked to physiological and molecular phenotypes, such as microbiota composition.
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http://dx.doi.org/10.15252/msb.20209684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792507PMC
January 2021

The Genetic Architecture of Carbon Tetrachloride-Induced Liver Fibrosis in Mice.

Cell Mol Gastroenterol Hepatol 2021 28;11(1):199-220. Epub 2020 Aug 28.

Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA and Pfleger Liver Institute, David Geffen School of Medicine at UCLA, Los Angeles, California. Electronic address:

Background & Aims: Liver fibrosis is a multifactorial trait that develops in response to chronic liver injury. Our aim was to characterize the genetic architecture of carbon tetrachloride (CCl)-induced liver fibrosis using the Hybrid Mouse Diversity Panel, a panel of more than 100 genetically distinct mouse strains optimized for genome-wide association studies and systems genetics.

Methods: Chronic liver injury was induced by CCl injections twice weekly for 6 weeks. Four hundred thirty-seven mice received CCl and 256 received vehicle, after which animals were euthanized for liver histology and gene expression. Using automated digital image analysis, we quantified fibrosis as the collagen proportionate area of the whole section, excluding normal collagen.

Results: We discovered broad variation in fibrosis among the Hybrid Mouse Diversity Panel strains, demonstrating a significant genetic influence. Genome-wide association analyses revealed significant and suggestive loci underlying susceptibility to fibrosis, some of which overlapped with loci identified in mouse crosses and human population studies. Liver global gene expression was assessed by RNA sequencing across the strains, and candidate genes were identified using differential expression and expression quantitative trait locus analyses. Gene set enrichment analyses identified the underlying pathways, of which stellate cell involvement was prominent, and coexpression network modeling identified modules associated with fibrosis.

Conclusions: Our results provide a rich resource for the design of experiments to understand mechanisms underlying fibrosis and for rational strain selection when testing antifibrotic drugs.
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http://dx.doi.org/10.1016/j.jcmgh.2020.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674618PMC
August 2020

Gene-by-Sex Interactions in Mitochondrial Functions and Cardio-Metabolic Traits.

Cell Metab 2019 04 10;29(4):932-949.e4. Epub 2019 Jan 10.

Department of Medicine/Division of Cardiology and Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address:

We studied sex differences in over 50 cardio-metabolic traits in a panel of 100 diverse inbred strains of mice. The results clearly showed that the effects of sex on both clinical phenotypes and gene expression depend on the genetic background. In support of this, genetic loci associated with the traits frequently showed sex specificity. For example, Lyplal1, a gene implicated in human obesity, was shown to underlie a sex-specific locus for diet-induced obesity. Global gene expression analyses of tissues across the panel implicated adipose tissue "beiging" and mitochondrial functions in the sex differences. Isolated mitochondria showed gene-by-sex interactions in oxidative functions, such that some strains (C57BL/6J) showed similar function between sexes, whereas others (DBA/2J and A/J) showed increased function in females. Reduced adipose mitochondrial function in males as compared to females was associated with increased susceptibility to obesity and insulin resistance. Gonadectomy studies indicated that gonadal hormones acting in a tissue-specific manner were responsible in part for the sex differences.
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http://dx.doi.org/10.1016/j.cmet.2018.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447452PMC
April 2019

Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease.

Biol Sex Differ 2018 10 22;9(1):46. Epub 2018 Oct 22.

Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.

Background: Non-alcoholic fatty liver disease (NAFLD) encompasses benign steatosis and more severe conditions such as non-alcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. This chronic liver disease has a poorly understood etiology and demonstrates sexual dimorphisms. We aim to examine the molecular mechanisms underlying sexual dimorphisms in NAFLD pathogenesis through a comprehensive multi-omics study. We integrated genomics (DNA variations), transcriptomics of liver and adipose tissue, and phenotypic data of NAFLD derived from female mice of ~ 100 strains included in the hybrid mouse diversity panel (HMDP) and compared the NAFLD molecular pathways and gene networks between sexes.

Results: We identified both shared and sex-specific biological processes for NAFLD. Adaptive immunity, branched chain amino acid metabolism, oxidative phosphorylation, and cell cycle/apoptosis were shared between sexes. Among the sex-specific pathways were vitamins and cofactors metabolism and ion channel transport for females, and phospholipid, lysophospholipid, and phosphatidylinositol metabolism and insulin signaling for males. Additionally, numerous lipid and insulin-related pathways and inflammatory processes in the adipose and liver tissue appeared to show more prominent association with NAFLD in male HMDP. Using data-driven network modeling, we identified plausible sex-specific and tissue-specific regulatory genes as well as those that are shared between sexes. These key regulators orchestrate the NAFLD pathways in a sex- and tissue-specific manner. Gonadectomy experiments support that sex hormones may partially underlie the sexually dimorphic genes and pathways involved in NAFLD.

Conclusions: Our multi-omics integrative study reveals sex- and tissue-specific genes, processes, and networks underlying sexual dimorphism in NAFLD and may facilitate sex-specific precision medicine.
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http://dx.doi.org/10.1186/s13293-018-0205-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196429PMC
October 2018

Systems Genetics Approach to Biomarker Discovery: GPNMB and Heart Failure in Mice and Humans.

G3 (Bethesda) 2018 11 6;8(11):3499-3506. Epub 2018 Nov 6.

Department of Medicine, Division of Cardiology

We describe a simple bioinformatics method for biomarker discovery that is based on the analysis of global transcript levels in a population of inbred mouse strains showing variation for disease-related traits. This method has advantages such as controlled environment and accessibility to heart and plasma tissue in the preclinical selection stage. We illustrate the approach by identifying candidate heart failure (HF) biomarkers by overlaying mouse transcriptome and clinical traits from 91 Hybrid Mouse Diversity Panel (HMDP) inbred strains and human HF transcriptome from the Myocardial Applied Genomics Network (MAGNet) consortium. We found that some of the top differentially expressed genes correlated with known human HF biomarkers, such as galectin-3 and tissue inhibitor of metalloproteinase 1. Using ELISA assays, we investigated one novel candidate, Glycoprotein NMB, in a mouse model of chronic β-adrenergic stimulation by isoproterenol (ISO) induced HF. We observed significantly lower GPNMB plasma levels in the ISO model compared to the control group (p-value = 0.007). In addition, we assessed GPNMB plasma levels among 389 HF cases and controls from the METabolic Syndrome In Men (METSIM) study. Lower levels of GPNMB were also observed in patients with HF from the METSIM study compared to non-HF controls (p-value < 0.0001). In summary, we have identified several candidate biomarkers for HF using the cardiac transcriptome data in a population of mice that may be directly relevant and applicable to human populations.
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http://dx.doi.org/10.1534/g3.118.200655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222577PMC
November 2018

The Genetic Architecture of Diet-Induced Hepatic Fibrosis in Mice.

Hepatology 2018 12 8;68(6):2182-2196. Epub 2018 Nov 8.

Department of Medicine, Division of Cardiology, David Geffen School of Medicine, Los Angeles, CA.

We report the genetic analysis of a "humanized" hyperlipidemic mouse model for progressive nonalcoholic steatohepatitis (NASH) and fibrosis. Mice carrying transgenes for human apolipoprotein E*3-Leiden and cholesteryl ester transfer protein and fed a "Western" diet were studied on the genetic backgrounds of over 100 inbred mouse strains. The mice developed hepatic inflammation and fibrosis that was highly dependent on genetic background, with vast differences in the degree of fibrosis. Histological analysis showed features characteristic of human NASH, including macrovesicular steatosis, hepatocellular ballooning, inflammatory foci, and pericellular collagen deposition. Time course experiments indicated that while hepatic triglyceride levels increased steadily on the diet, hepatic fibrosis occurred at about 12 weeks. We found that the genetic variation predisposing to NASH and fibrosis differs markedly from that predisposing to simple steatosis, consistent with a multistep model in which distinct genetic factors are involved. Moreover, genome-wide association identified distinct genetic loci contributing to steatosis and NASH. Finally, we used hepatic expression data from the mouse panel and from 68 bariatric surgery patients with normal liver, steatosis, or NASH to identify enriched biological pathways. Conclusion: The pathways showed substantial overlap between our mouse model and the human disease.
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http://dx.doi.org/10.1002/hep.30113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269199PMC
December 2018

Genetic, dietary, and sex-specific regulation of hepatic ceramides and the relationship between hepatic ceramides and IR.

J Lipid Res 2018 07 8;59(7):1164-1174. Epub 2018 May 8.

Division of Cardiology University of California at Los Angeles, Los Angeles, CA

Elevated hepatic ceramide levels have been implicated in both insulin resistance (IR) and hepatic steatosis. To understand the factors contributing to hepatic ceramide levels in mice of both sexes, we have quantitated ceramides in a reference population of mice, the Hybrid Mouse Diversity Panel that has been previously characterized for a variety of metabolic syndrome traits. We observed significant positive correlations between Cer(d18:1/16:0) and IR/hepatic steatosis, consistent with previous findings, although the relationship broke down between sexes, as females were less insulin resistant, but had higher Cer(d18:1/16:0) levels than males. The sex difference was due in part to testosterone-mediated repression of ceramide synthase 6. One ceramide species, Cer(d18:1/20:0), was present at higher levels in males and was associated with IR only in males. Clear evidence of gene-by-sex and gene-by-diet interactions was observed, including sex-specific genome-wide association study results. Thus, our studies show clear differences in how hepatic ceramides are regulated between the sexes, which again suggests that the physiological roles of certain hepatic ceramides differ between the sexes.
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http://dx.doi.org/10.1194/jlr.M081398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027922PMC
July 2018

Integration of Multi-omics Data from Mouse Diversity Panel Highlights Mitochondrial Dysfunction in Non-alcoholic Fatty Liver Disease.

Cell Syst 2018 Jan 18;6(1):103-115.e7. Epub 2018 Jan 18.

Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA; Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA, USA. Electronic address:

The etiology of non-alcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease, is poorly understood. To understand the causal mechanisms underlying NAFLD, we conducted a multi-omics, multi-tissue integrative study using the Hybrid Mouse Diversity Panel, consisting of ∼100 strains of mice with various degrees of NAFLD. We identified both tissue-specific biological processes and processes that were shared between adipose and liver tissues. We then used gene network modeling to predict candidate regulatory genes of these NAFLD processes, including Fasn, Thrsp, Pklr, and Chchd6. In vivo knockdown experiments of the candidate genes improved both steatosis and insulin resistance. Further in vitro testing demonstrated that downregulation of both Pklr and Chchd6 lowered mitochondrial respiration and led to a shift toward glycolytic metabolism, thus highlighting mitochondria dysfunction as a key mechanistic driver of NAFLD.
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http://dx.doi.org/10.1016/j.cels.2017.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799036PMC
January 2018

mRNA and plasma hepcidin levels are influenced by sex and strain but do not predict tissue iron levels in inbred mice.

Am J Physiol Gastrointest Liver Physiol 2017 Nov 10;313(5):G511-G523. Epub 2017 Aug 10.

Department of Nutritional Science & Toxicology, University of California, Berkeley, California.

Iron homeostasis is tightly regulated, and the peptide hormone hepcidin is considered to be a principal regulator of iron metabolism. Previous studies in a limited number of mouse strains found equivocal sex- and strain-dependent differences in mRNA and serum levels of hepcidin and reported conflicting data on the relationship between hepcidin () mRNA levels and iron status. Our aim was to clarify the relationships between strain, sex, and hepcidin expression by examining multiple tissues and the effects of different dietary conditions in multiple inbred strains. Two studies were done: first, mRNA, liver iron, and plasma diferric transferrin levels were measured in 14 inbred strains on a control diet; and second, mRNA and plasma hepcidin levels in both sexes and iron levels in the heart, kidneys, liver, pancreas, and spleen in males were measured in nine inbred/recombinant inbred strains raised on an iron-sufficient or high-iron diet. Both sex and strain have a significant effect on both hepcidin mRNA (primarily a sex effect) and plasma hepcidin levels (primarily a strain effect). However, liver iron and diferric transferrin levels are not predictors of mRNA levels in mice fed iron-sufficient or high-iron diets, nor are the mRNA and plasma hepcidin levels good predictors of tissue iron levels, at least in males. We also measured plasma erythroferrone, performed RNA-sequencing analysis of liver samples from six inbred strains fed the iron-sufficient, low-iron, or high-iron diets, and explored differences in gene expression between the strains with the highest and lowest hepcidin levels. Both sex and strain have a significant effect on both hepcidin mRNA (primarily a sex effect) and plasma hepcidin levels (primarily a strain effect). Liver iron and diferric transferrin levels are not predictors of mRNA levels in mice, nor are the mRNA and plasma hepcidin levels good predictors of tissue iron levels, at least in males.
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http://dx.doi.org/10.1152/ajpgi.00307.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792216PMC
November 2017

Genetic and hormonal control of hepatic steatosis in female and male mice.

J Lipid Res 2017 01 3;58(1):178-187. Epub 2016 Nov 3.

Department of Medicine, Division of Cardiology, University of California at Los Angeles, Los Angeles, CA

The etiology of nonalcoholic fatty liver disease is complex and influenced by factors such as obesity, insulin resistance, hyperlipidemia, and sex. We now report a study on sex difference in hepatic steatosis in the context of genetic variation using a population of inbred strains of mice. While male mice generally exhibited higher concentration of hepatic TG levels on a high-fat high-sucrose diet, sex differences showed extensive interaction with genetic variation. Differences in percentage body fat were the best predictor of hepatic steatosis among the strains and explained about 30% of the variation in both sexes. The difference in percent gonadal fat and HDL explained 9.6% and 6.7% of the difference in hepatic TGs between the sexes, respectively. Genome-wide association mapping of hepatic TG revealed some striking differences in genetic control of hepatic steatosis between females and males. Gonadectomy increased the hepatic TG to body fat percentage ratio among male, but not female, mice. Our data suggest that the difference between the sexes in hepatic TG can be partly explained by differences in body fat distribution, plasma HDL, and genetic regulation. Future studies are required to understand the molecular interactions between sex, genetics, and the environment.
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http://dx.doi.org/10.1194/jlr.M071522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234719PMC
January 2017

The Hybrid Mouse Diversity Panel: a resource for systems genetics analyses of metabolic and cardiovascular traits.

J Lipid Res 2016 06 19;57(6):925-42. Epub 2016 Apr 19.

Departments of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA.

The Hybrid Mouse Diversity Panel (HMDP) is a collection of approximately 100 well-characterized inbred strains of mice that can be used to analyze the genetic and environmental factors underlying complex traits. While not nearly as powerful for mapping genetic loci contributing to the traits as human genome-wide association studies, it has some important advantages. First, environmental factors can be controlled. Second, relevant tissues are accessible for global molecular phenotyping. Finally, because inbred strains are renewable, results from separate studies can be integrated. Thus far, the HMDP has been studied for traits relevant to obesity, diabetes, atherosclerosis, osteoporosis, heart failure, immune regulation, fatty liver disease, and host-gut microbiota interactions. High-throughput technologies have been used to examine the genomes, epigenomes, transcriptomes, proteomes, metabolomes, and microbiomes of the mice under various environmental conditions. All of the published data are available and can be readily used to formulate hypotheses about genes, pathways and interactions.
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http://dx.doi.org/10.1194/jlr.R066944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878195PMC
June 2016

The genetic architecture of NAFLD among inbred strains of mice.

Elife 2015 Jun 12;4:e05607. Epub 2015 Jun 12.

Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.

To identify genetic and environmental factors contributing to the pathogenesis of non-alcoholic fatty liver disease, we examined liver steatosis and related clinical and molecular traits in more than 100 unique inbred mouse strains, which were fed a diet rich in fat and carbohydrates. A >30-fold variation in hepatic TG accumulation was observed among the strains. Genome-wide association studies revealed three loci associated with hepatic TG accumulation. Utilizing transcriptomic data from the liver and adipose tissue, we identified several high-confidence candidate genes for hepatic steatosis, including Gde1, a glycerophosphodiester phosphodiesterase not previously implicated in triglyceride metabolism. We confirmed the role of Gde1 by in vivo hepatic over-expression and shRNA knockdown studies. We hypothesize that Gde1 expression increases TG production by contributing to the production of glycerol-3-phosphate. Our multi-level data, including transcript levels, metabolite levels, and gut microbiota composition, provide a framework for understanding genetic and environmental interactions underlying hepatic steatosis.
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http://dx.doi.org/10.7554/eLife.05607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493743PMC
June 2015

Txnip ablation reduces vascular smooth muscle cell inflammation and ameliorates atherosclerosis in apolipoprotein E knockout mice.

Atherosclerosis 2015 Aug 3;241(2):313-21. Epub 2015 Jun 3.

Division of Cardiology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

Objective: Inflammation of vascular smooth muscle cells (VSMC) is intimately linked to atherosclerosis and other vascular inflammatory disease. Thioredoxin interacting protein (Txnip) is a key regulator of cellular sulfhydryl redox and a mediator of inflammasome activation. The goals of the present study were to examine the impact of Txnip ablation on inflammatory response to oxidative stress in VSMC and to determine the effect of Txnip ablation on atherosclerosis in vivo.

Methods And Results: Using cultured VSMC, we showed that ablation of Txnip reduced cellular oxidative stress and increased protection from oxidative stress when challenged with oxidized phospholipids and hydrogen peroxide. Correspondingly, expression of inflammatory markers and adhesion molecules were diminished in both VSMC and macrophages from Txnip knockout mice. The blunted inflammatory response was associated with a decrease in NF-ĸB nuclear translocation. Loss of Txnip in VSMC also led to a dramatic reduction in macrophage adhesion to VSMC. In vivo data from Txnip-ApoE double knockout mice showed that Txnip ablation led to 49% reduction in atherosclerotic lesion in the aortic root and 71% reduction in the abdominal aorta, compared to control ApoE knockout mice.

Conclusion: Our data show that Txnip plays an important role in oxidative inflammatory response and atherosclerotic lesion development in mice. The atheroprotective effect of Txnip ablation implicates that modulation of Txnip expression may serve as a potential target for intervention of atherosclerosis and inflammatory vascular disease.
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http://dx.doi.org/10.1016/j.atherosclerosis.2015.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509824PMC
August 2015

Genetic architecture of insulin resistance in the mouse.

Cell Metab 2015 Feb;21(2):334-347

Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

Insulin resistance (IR) is a complex trait with multiple genetic and environmental components. Confounded by large differences between the sexes, environment, and disease pathology, the genetic basis of IR has been difficult to dissect. Here we examine IR and related traits in a diverse population of more than 100 unique male and female inbred mouse strains after feeding a diet rich in fat and refined carbohydrates. Our results show dramatic variation in IR among strains of mice and widespread differences between sexes that are dependent on genotype. We uncover more than 15 genome-wide significant loci and validate a gene, Agpat5, associated with IR. We also integrate plasma metabolite levels and global gene expression from liver and adipose tissue to identify metabolite quantitative trait loci (mQTL) and expression QTL (eQTL), respectively. Our results provide a resource for analysis of interactions between diet, sex, and genetic background in IR.
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http://dx.doi.org/10.1016/j.cmet.2015.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349439PMC
February 2015

Thioredoxin-interacting protein regulates the differentiation of murine erythroid precursors.

Exp Hematol 2015 May 16;43(5):393-403.e2. Epub 2015 Jan 16.

Lady Davis Institute for Medical Research, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of Physiology, McGill University, Montreal, Quebec, Canada. Electronic address:

Thioredoxin-interacting protein (TXNIP) is involved in various cellular processes including redox control, metabolism, differentiation, growth, and apoptosis. With respect to hematopoiesis, TXNIP has been shown to play roles in natural killer cells, dendritic cells, and hematopoietic stem cells. Our study investigates the role of TXNIP in erythropoiesis. We observed a rapid and significant increase of TXNIP transcript and protein levels in mouse erythroleukemia cells treated with dimethyl sulfoxide or hexamethylene bisacetamide, inducers of erythroid differentiation. The upregulation of TXNIP was not abrogated by addition of the antioxidant N-acetylcysteine. The increase of TXNIP expression was confirmed in another model of erythroid differentiation, G1E-ER cells, which undergo differentiation upon activation of the GATA1 transcription factor. In addition, we showed that TXNIP levels are induced following inhibition of p38 or c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases. We also observed an increase in iron uptake and a decrease in transferrin receptor protein upon TXNIP overexpression, suggesting a role in iron homeostasis. In vivo, flow cytometry analysis of cells from Txnip(-/-) mice revealed a new phenotype of impaired terminal erythropoiesis in the spleen, characterized by a partial block between basophilic and late basophilic/polychromatic erythroblasts. Based on our data, TXNIP emerges as a novel regulator of terminal erythroid differentiation.
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http://dx.doi.org/10.1016/j.exphem.2015.01.003DOI Listing
May 2015

Targeted metabolomics connects thioredoxin-interacting protein (TXNIP) to mitochondrial fuel selection and regulation of specific oxidoreductase enzymes in skeletal muscle.

J Biol Chem 2014 Mar 30;289(12):8106-20. Epub 2014 Jan 30.

From the Sarah W. Stedman Nutrition and Metabolism Center.

Thioredoxin-interacting protein (TXNIP) is an α-arrestin family member involved in redox sensing and metabolic control. Growing evidence links TXNIP to mitochondrial function, but the molecular nature of this relationship has remained poorly defined. Herein, we employed targeted metabolomics and comprehensive bioenergetic analyses to evaluate oxidative metabolism and respiratory kinetics in mouse models of total body (TKO) and skeletal muscle-specific (TXNIP(SKM-/-)) Txnip deficiency. Compared with littermate controls, both TKO and TXNIP(SKM-/-) mice had reduced exercise tolerance in association with muscle-specific impairments in substrate oxidation. Oxidative insufficiencies in TXNIP null muscles were not due to perturbations in mitochondrial mass, the electron transport chain, or emission of reactive oxygen species. Instead, metabolic profiling analyses led to the discovery that TXNIP deficiency causes marked deficits in enzymes required for catabolism of branched chain amino acids, ketones, and lactate, along with more modest reductions in enzymes of β-oxidation and the tricarboxylic acid cycle. The decrements in enzyme activity were accompanied by comparable deficits in protein abundance without changes in mRNA expression, implying dysregulation of protein synthesis or stability. Considering that TXNIP expression increases in response to starvation, diabetes, and exercise, these findings point to a novel role for TXNIP in coordinating mitochondrial fuel switching in response to nutrient availability.
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http://dx.doi.org/10.1074/jbc.M113.511535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961642PMC
March 2014

Induction of the metabolic regulator Txnip in fasting-induced and natural torpor.

Endocrinology 2013 Jun 12;154(6):2081-91. Epub 2013 Apr 12.

Faculty of Life Sciences, AV Hill Building, University of Manchester, Manchester M13 9PT, UK.

Torpor is a physiological state characterized by controlled lowering of metabolic rate and core body temperature, allowing substantial energy savings during periods of reduced food availability or harsh environmental conditions. The hypothalamus coordinates energy homeostasis and thermoregulation and plays a key role in directing torpor. We recently showed that mice lacking the orphan G protein-coupled receptor Gpr50 readily enter torpor in response to fasting and have now used these mice to conduct a microarray analysis of hypothalamic gene expression changes related to the torpor state. This revealed a strong induction of thioredoxin-interacting protein (Txnip) in the hypothalamus of torpid mice, which was confirmed by quantitative RT-PCR and Western blot analyses. In situ hybridization identified the ependyma lining the third ventricle as the principal site of torpor-related expression of Txnip. To characterize further the relationship between Txnip and torpor, we profiled Txnip expression in mice during prolonged fasting, cold exposure, and 2-deoxyglucose-induced hypometabolism, as well as in naturally occurring torpor bouts in the Siberian hamster. Strikingly, pronounced up-regulation of Txnip expression was only observed in wild-type mice when driven into torpor and during torpor in the Siberian hamster. Increase of Txnip was not limited to the hypothalamus, with exaggerated expression in white adipose tissue, brown adipose tissue, and liver also demonstrated in torpid mice. Given the recent identification of Txnip as a molecular nutrient sensor important in the regulation of energy metabolism, our data suggest that elevated Txnip expression is critical to regulating energy expenditure and fuel use during the extreme hypometabolic state of torpor.
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http://dx.doi.org/10.1210/en.2012-2051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740491PMC
June 2013

Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice.

Cell Metab 2013 Jan;17(1):141-52

Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Obesity is a highly heritable disease driven by complex interactions between genetic and environmental factors. Human genome-wide association studies (GWAS) have identified a number of loci contributing to obesity; however, a major limitation of these studies is the inability to assess environmental interactions common to obesity. Using a systems genetics approach, we measured obesity traits, global gene expression, and gut microbiota composition in response to a high-fat/high-sucrose (HF/HS) diet of more than 100 inbred strains of mice. Here we show that HF/HS feeding promotes robust, strain-specific changes in obesity that are not accounted for by food intake and provide evidence for a genetically determined set point for obesity. GWAS analysis identified 11 genome-wide significant loci associated with obesity traits, several of which overlap with loci identified in human studies. We also show strong relationships between genotype and gut microbiota plasticity during HF/HS feeding and identify gut microbial phylotypes associated with obesity.
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http://dx.doi.org/10.1016/j.cmet.2012.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545283PMC
January 2013

Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traits.

Mamm Genome 2012 Oct 15;23(9-10):680-92. Epub 2012 Aug 15.

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

We have developed an association-based approach using classical inbred strains of mice in which we correct for population structure, which is very extensive in mice, using an efficient mixed-model algorithm. Our approach includes inbred parental strains as well as recombinant inbred strains in order to capture loci with effect sizes typical of complex traits in mice (in the range of 5% of total trait variance). Over the last few years, we have typed the hybrid mouse diversity panel (HMDP) strains for a variety of clinical traits as well as intermediate phenotypes and have shown that the HMDP has sufficient power to map genes for highly complex traits with resolution that is in most cases less than a megabase. In this essay, we review our experience with the HMDP, describe various ongoing projects, and discuss how the HMDP may fit into the larger picture of common diseases and different approaches.
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http://dx.doi.org/10.1007/s00335-012-9411-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586763PMC
October 2012

Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome.

Cell Metab 2012 Aug;16(2):265-73

Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Recent clinical and experimental evidence suggests that endoplasmic reticulum (ER) stress contributes to the life-and-death decisions of β cells during the progression of type 1 and type 2 diabetes. Although crosstalk between inflammation and ER stress has been suggested to play a significant role in β cell dysfunction and death, a key molecule connecting ER stress to inflammation has not been identified. Here we report that thioredoxin-interacting protein (TXNIP) is a critical signaling node that links ER stress and inflammation. TXNIP is induced by ER stress through the PERK and IRE1 pathways, induces IL-1β mRNA transcription, activates IL-1β production by the NLRP3 inflammasome, and mediates ER stress-mediated β cell death. Collectively, our results suggest that TXNIP is a potential therapeutic target for diabetes and ER stress-related human diseases such as Wolfram syndrome.
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http://dx.doi.org/10.1016/j.cmet.2012.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418541PMC
August 2012

IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress.

Cell Metab 2012 Aug;16(2):250-64

Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.

When unfolded proteins accumulate to irremediably high levels within the endoplasmic reticulum (ER), intracellular signaling pathways called the unfolded protein response (UPR) become hyperactivated to cause programmed cell death. We discovered that thioredoxin-interacting protein (TXNIP) is a critical node in this "terminal UPR." TXNIP becomes rapidly induced by IRE1α, an ER bifunctional kinase/endoribonuclease (RNase). Hyperactivated IRE1α increases TXNIP mRNA stability by reducing levels of a TXNIP destabilizing microRNA, miR-17. In turn, elevated TXNIP protein activates the NLRP3 inflammasome, causing procaspase-1 cleavage and interleukin 1β (IL-1β) secretion. Txnip gene deletion reduces pancreatic β cell death during ER stress and suppresses diabetes caused by proinsulin misfolding in the Akita mouse. Finally, small molecule IRE1α RNase inhibitors suppress TXNIP production to block IL-1β secretion. In summary, the IRE1α-TXNIP pathway is used in the terminal UPR to promote sterile inflammation and programmed cell death and may be targeted to develop effective treatments for cell degenerative diseases.
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http://dx.doi.org/10.1016/j.cmet.2012.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014071PMC
August 2012

Diminished AMPK signaling response to fasting in thioredoxin-interacting protein knockout mice.

FEBS Lett 2011 Apr 23;585(8):1223-30. Epub 2011 Mar 23.

Department of Biology, BioScience Center, San Diego State University, San Diego, CA 92182, USA.

Thioredoxin-interacting protein (Txnip) knockout (TKO) mice exhibit impaired response to fasting. Herein, we showed that activation of adenine monophosphate-activated protein kinase and cellular AMP levels were diminished in the heart and soleus muscle but not in gastrocnemius muscle of fasting TKO mice. Similarly, glycogen content in fasted TKO mice was increased in oxidative muscles but was not different in glycolytic muscles. These data suggest Txnip deficiency has a higher impact on oxidative muscle than glycolytic muscles and provide new insights into the metabolic role of Txnip.
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http://dx.doi.org/10.1016/j.febslet.2011.03.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088363PMC
April 2011

Thioredoxin-interacting protein deficiency induces Akt/Bcl-xL signaling and pancreatic beta-cell mass and protects against diabetes.

FASEB J 2008 Oct 13;22(10):3581-94. Epub 2008 Jun 13.

Department of Medicine, University of Wisconsin, Madison, Wisconsin 53792, USA.

Pancreatic beta-cell loss through apoptosis represents a key factor in the pathogenesis of diabetes; however, no effective approaches to block this process and preserve endogenous beta-cell mass are currently available. To study the role of thioredoxin-interacting protein (TXNIP), a proapoptotic beta-cell factor we recently identified, we used HcB-19 (TXNIP nonsense mutation) and beta-cell-specific TXNIP knockout (bTKO) mice. Interestingly, HcB-19 mice demonstrate increased adiposity, but have lower blood glucose levels and increased pancreatic beta-cell mass (as assessed by morphometry). Moreover, HcB-19 mice are resistant to streptozotocin-induced diabetes. When intercrossed with obese, insulin-resistant, and diabetic mice, double-mutant BTBRlep(ob/ob)txnip(hcb/hcb) are even more obese, but are protected against diabetes and beta-cell apoptosis, resulting in a 3-fold increase in beta-cell mass. Beta-cell-specific TXNIP deletion also enhanced beta-cell mass (P<0.005) and protected against diabetes, and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) revealed a approximately 50-fold reduction in beta-cell apoptosis in streptozotocin-treated bTKO mice. We further discovered that TXNIP deficiency induces Akt/Bcl-xL signaling and inhibits mitochondrial beta-cell death, suggesting that these mechanisms may mediate the beta-cell protective effects of TXNIP deficiency. These results suggest that lowering beta-cell TXNIP expression could serve as a novel strategy for the treatment of type 1 and type 2 diabetes by promoting endogenous beta-cell survival.
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http://dx.doi.org/10.1096/fj.08-111690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2537437PMC
October 2008

Txnip balances metabolic and growth signaling via PTEN disulfide reduction.

Proc Natl Acad Sci U S A 2008 Mar 5;105(10):3921-6. Epub 2008 Mar 5.

Department of Biology, The Molecular Biology and Heart Institutes, The BioSciences Center, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182, USA.

Thioredoxin-interacting protein (Txnip) inhibits thioredoxin NADPH-dependent reduction of protein disulfides. Total Txnip knockout (TKO) mice adapted inappropriately to prolonged fasting by shifting fuel dependence of skeletal muscle and heart from fat and ketone bodies to glucose. TKO mice exhibited increased Akt signaling, insulin sensitivity, and glycolysis in oxidative tissues (skeletal muscle and hearts) but not in lipogenic tissues (liver and adipose tissue). The selective activation of Akt in skeletal muscle and hearts was associated with impaired mitochondrial fuel oxidation and the accumulation of oxidized (inactive) PTEN, whose activity depends on reduction of two critical cysteine residues. Whereas muscle- and heart-specific Txnip knockout mice recapitulated the metabolic phenotype exhibited by TKO mice, liver-specific Txnip knockout mice were similar to WT mice. Embryonic fibroblasts derived from knockout mice also accumulated oxidized (inactive) PTEN and had elevated Akt phosphorylation. In addition, they had faster growth rates and increased dependence on anaerobic glycolysis due to impaired mitochondrial fuel oxidation, and they were resistant to doxorubicin-facilitated respiration-dependent apoptosis. In the absence of Txnip, oxidative inactivation of PTEN and subsequent activation of Akt attenuated mitochondrial respiration, resulting in the accumulation of NADH, a competitive inhibitor of thioredoxin NADPH-reductive activation of PTEN. These findings indicate that, in nonlipogenic tissues, Txnip is required to maintain sufficient thioredoxin NADPH activity to reductively reactivate oxidized PTEN and oppose Akt downstream signaling.
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http://dx.doi.org/10.1073/pnas.0800293105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268825PMC
March 2008

Coordinate transcriptional repression of liver fatty acid-binding protein and microsomal triglyceride transfer protein blocks hepatic very low density lipoprotein secretion without hepatosteatosis.

J Biol Chem 2006 Nov 31;281(44):33066-77. Epub 2006 Aug 31.

Department of Biology, The Heart Institute, San Diego State University, California 92182-4614, USA.

Unlike the livers of humans and mice, and most hepatoma cells, which accumulate triglycerides when treated with microsomal triglyceride transfer protein (MTP) inhibitors, L35 rat hepatoma cells do not express MTP and cannot secrete very low density lipoprotein (VLDL), yet they do not accumulate triglyceride. In these studies we show that transcriptional co-repression of the two lipid transfer proteins, liver fatty acid-binding protein (L-FABP) and MTP, which cooperatively shunt fatty acids into de novo synthesized glycerolipids and the transfer of lipids into VLDL, respectively, act together to maintain hepatic lipid homeostasis. FAO rat hepatoma cells express L-FABP and MTP and demonstrate the ability to assemble and secrete VLDL. In contrast, L35 cells, derived as a single cell clone from FAO cells, do not express L-FABP or MTP nor do they assemble and secrete VLDL. We used these hepatoma cells to elucidate how a conserved DR1 promoter element present in the promoters of L-FABP and MTP affects transcription, expression, and VLDL production. In FAO cells, the DR1 elements of both L-FABP and MTP promoters are occupied by peroxisome proliferator-activated receptor alpha-retinoid X receptor alpha (RXRalpha), with which PGC-1beta activates transcription. In contrast, in L35 cells the DR1 elements of both L-FABP and MTP promoters are occupied by chicken ovalbumin upstream promoter transcription factor II, and transcription is diminished. The combined findings indicate that peroxisome proliferator-activated receptor alpha-RXRalpha and PGC-1beta coordinately up-regulate L-FABP and MTP expression, by competing with chicken ovalbumin upstream promoter transcription factor II for the DR1 sites in the proximal promoters of each gene. Additional studies show that ablation of L-FABP prevents hepatic steatosis caused by treating mice with an MTP inhibitor. Our findings show that reducing both L-FABP and MTP is an effective means to reduce VLDL secretion without causing hepatic steatosis.
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http://dx.doi.org/10.1074/jbc.M607148200DOI Listing
November 2006