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1. Conserved multi-tissue transcriptomic adaptations to exercise training in humans and mice

Author

Moore, Timothy M, Lee, Sindre, Olsen, Thomas, Morselli, Marco, Strumwasser, Alexander R, Lin, Amanda J, Zhou, Zhenqi, Abrishami, Aaron, Garcia, Steven M, Bribiesca, Jennifer, Cory, Kevin, Whitney, Kate, Ho, Theodore, Ho, Timothy, Lee, Joseph L, Rucker, Daniel H, Nguyen, Christina QA, Anand, Akshay TS, Yackly, Aidan, Mendoza, Lorna Q, Leyva, Brayden K, Aliman, Claudia, Artiga, Daniel J, Meng, Yonghong, Charugundla, Sarada, Pan, Calvin, Jedian, Vida, Seldin, Marcus M, Ahn, In Sook, Diamante, Graciel, Blencowe, Montgomery, Yang, Xia, Mouisel, Etienne, Pellegrini, Matteo, Turcotte, Lorraine P, Birkeland, Kåre I, Norheim, Frode, Drevon, Christian A, Lusis, Aldons J, and Hevener, Andrea L

Subjects
Biological Sciences, Genetics, Prevention, Human Genome, Physical Activity, Nutrition, Obesity, 2.1 Biological and endogenous factors, Metabolic and endocrine, Oral and gastrointestinal, Male, Middle Aged, Humans, Female, Mice, Animals, Transcriptome, Adaptation, Physiological, Acclimatization, Adipose Tissue, Muscle, Skeletal, CP: Metabolism, CP: Molecular biology, HMDP, exercise, genetics, multi-omics, physical activity, physiology, systems biology, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract

Physical activity is associated with beneficial adaptations in human and rodent metabolism. We studied over 50 complex traits before and after exercise intervention in middle-aged men and a panel of 100 diverse strains of female mice. Candidate gene analyses in three brain regions, muscle, liver, heart, and adipose tissue of mice indicate genetic drivers of clinically relevant traits, including volitional exercise volume, muscle metabolism, adiposity, and hepatic lipids. Although ∼33% of genes differentially expressed in skeletal muscle following the exercise intervention are similar in mice and humans independent of BMI, responsiveness of adipose tissue to exercise-stimulated weight loss appears controlled by species and underlying genotype. We leveraged genetic diversity to generate prediction models of metabolic trait responsiveness to volitional activity offering a framework for advancing personalized exercise prescription. The human and mouse data are publicly available via a user-friendly Web-based application to enhance data mining and hypothesis development.

Published
2023

2. Effect of voluntary exercise upon the metabolic syndrome and gut microbiome composition in mice

Author

Moore, Timothy M, Terrazas, Anthony, Strumwasser, Alexander R, Lin, Amanda J, Zhu, Xiaopeng, Anand, Akshay TS, Nguyen, Christina Q, Stiles, Linsey, Norheim, Frode, Lang, Jennifer M, Hui, Simon T, Turcotte, Lorraine P, and Zhou, Zhenqi

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Digestive Diseases, Physical Activity, Obesity, Cardiovascular, Diabetes, Prevention, Nutrition, Microbiome, Aging, Liver Disease, 2.1 Biological and endogenous factors, Metabolic and endocrine, Oral and gastrointestinal, Adiposity, Animals, Gastrointestinal Microbiome, Glucose, Liver, Male, Metabolic Syndrome, Mice, Mice, Inbred C57BL, Mitochondria, Liver, Physical Conditioning, Animal, Receptors, LDL, Running, exercise, LDLR, metabolic syndrome, microbiome, obesity, Physiology, Clinical Sciences, Medical physiology
Abstract

The metabolic syndrome is a cluster of conditions that increase an individual's risk of developing diseases. Being physically active throughout life is known to reduce the prevalence and onset of some aspects of the metabolic syndrome. Furthermore, previous studies have demonstrated that an individual's gut microbiome composition has a large influence on several aspects of the metabolic syndrome. However, the mechanism(s) by which physical activity may improve metabolic health are not well understood. We sought to determine if endurance exercise is sufficient to prevent or ameliorate the development of the metabolic syndrome and its associated diseases. We also analyzed the impact of physical activity under metabolic syndrome progression upon the gut microbiome composition. Utilizing whole-body low-density lipoprotein receptor (LDLR) knockout mice on a "Western Diet," we show that long-term exercise acts favorably upon glucose tolerance, adiposity, and liver lipids. Exercise increased mitochondrial abundance in skeletal muscle but did not reduce liver fibrosis, aortic lesion area, or plasma lipids. Lastly, we observed several changes in gut bacteria and their novel associations with metabolic parameters of clinical importance. Altogether, our results indicate that exercise can ameliorate some aspects of the metabolic syndrome progression and alter the gut microbiome composition.

Published
2021

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

Author

Norheim, Frode, Chella Krishnan, Karthickeyan, Bjellaas, Thomas, Vergnes, Laurent, Pan, Calvin, Parks, Brian W, Meng, Yonghong, Lang, Jennifer, Ward, James A, Reue, Karen, Mehrabian, Margarete, Gundersen, Thomas E, Péterfy, Miklós, Dalen, Knut T, Drevon, Christian A, Hui, Simon T, Lusis, Aldons J, and Seldin, Marcus M

Subjects
Biological Sciences, Genetics, Digestive Diseases, Chronic Liver Disease and Cirrhosis, Human Genome, Nutrition, Liver Disease, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Oral and gastrointestinal, Metabolic and endocrine, Animals, Diet, High-Fat, Disease Models, Animal, Fatty Liver, Gene Expression Profiling, Gene Expression Regulation, Genetic Variation, Glucose, Insulin Resistance, Lipidomics, MAP Kinase Kinase 6, Male, Mice, Nuclear Proteins, Phosphatidylcholines, Triglycerides, genome-wide association studies, hepatic lipidome, Hybrid Mouse Diversity Panel, non-alcoholic fatty liver disease, quantitative trait loci for lipids, Biochemistry and Cell Biology, Other Biological Sciences, Bioinformatics, Biochemistry and cell biology
Abstract

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.

Published
2021

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

Author

Chella Krishnan, Karthickeyan, Pan, Calvin, Mehrabian, Margarete, Zhou, Zhiqiang, Gupta, Sonul, Parks, Brian, Walch, Axel, Reue, Karen, Hofmann, Susanna, Arnold, Arthur, Norheim, Frode, Hasin-Brumshtein, Yehudit, Lusis, Aldons, Seldin, Marcus, Vergnes, Laurent, and Hui, Simon

Subjects
adipose tissue “browning”, gene-by-sex interactions, gonadectomy, hybrid mouse diversity panel, mitochondrial functions, sex differences, uncoupling protein-1, Adipose Tissue, Animals, Cardiovascular Diseases, Female, Insulin Resistance, Male, Mice, Mice, Inbred Strains, Mice, Transgenic, Mitochondria, Obesity, Phenotype, Principal Component Analysis, Sex Characteristics
Abstract

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.

Published
2019

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

Author

Norheim, Frode, Hasin-Brumshtein, Yehudit, Vergnes, Laurent, Chella Krishnan, Karthickeyan, Pan, Calvin, Seldin, Marcus M, Hui, Simon T, Mehrabian, Margarete, Zhou, Zhiqiang, Gupta, Sonul, Parks, Brian W, Walch, Axel, Reue, Karen, Hofmann, Susanna M, Arnold, Arthur P, and Lusis, Aldons J

Subjects
Adipose Tissue, Mitochondria, Animals, Mice, Inbred Strains, Mice, Transgenic, Mice, Cardiovascular Diseases, Insulin Resistance, Obesity, Sex Characteristics, Phenotype, Principal Component Analysis, Female, Male, adipose tissue “browning”, gene-by-sex interactions, gonadectomy, hybrid mouse diversity panel, mitochondrial functions, sex differences, uncoupling protein-1, Nutrition, Genetics, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Stroke, Metabolic and endocrine, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Endocrinology & Metabolism
Abstract

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.

Published
2019

6. The impact of exercise on mitochondrial dynamics and the role of Drp1 in exercise performance and training adaptations in skeletal muscle.

Author

Moore, Timothy M, Zhou, Zhenqi, Cohn, Whitaker, Norheim, Frode, Lin, Amanda J, Kalajian, Nareg, Strumwasser, Alexander R, Cory, Kevin, Whitney, Kate, Ho, Theodore, Ho, Timothy, Lee, Joseph L, Rucker, Daniel H, Shirihai, Orian, van der Bliek, Alexander M, Whitelegge, Julian P, Seldin, Marcus M, Lusis, Aldons J, Lee, Sindre, Drevon, Christian A, Mahata, Sushil K, Turcotte, Lorraine P, and Hevener, Andrea L

Subjects
Muscle, Skeletal, Mitochondria, Animals, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Humans, Mice, GTP Phosphohydrolases, Dynamins, Blood Glucose, Microtubule-Associated Proteins, Mitochondrial Proteins, Physical Conditioning, Animal, Adaptation, Physiological, Gene Deletion, Phosphorylation, Physical Endurance, Adult, Aged, Middle Aged, Female, Male, Mitochondrial Dynamics, Physical Functional Performance, Drp1, Exercise performance, Exercise training, Mitochondrial dynamics, Muscle, Skeletal, Inbred BALB C, Inbred C3H, Inbred C57BL, Physical Conditioning, Animal, Adaptation, Physiological, Biochemistry and Cell Biology, Physiology
Abstract

ObjectiveMitochondria are organelles primarily responsible for energy production, and recent evidence indicates that alterations in size, shape, location, and quantity occur in response to fluctuations in energy supply and demand. We tested the impact of acute and chronic exercise on mitochondrial dynamics signaling and determined the impact of the mitochondrial fission regulator Dynamin related protein (Drp)1 on exercise performance and muscle adaptations to training.MethodsWildtype and muscle-specific Drp1 heterozygote (mDrp1+/-) mice, as well as dysglycemic (DG) and healthy normoglycemic men (control) performed acute and chronic exercise. The Hybrid Mouse Diversity Panel, including 100 murine strains of recombinant inbred mice, was used to identify muscle Dnm1L (encodes Drp1)-gene relationships.ResultsEndurance exercise impacted all aspects of the mitochondrial life cycle, i.e. fission-fusion, biogenesis, and mitophagy. Dnm1L gene expression and Drp1Ser616 phosphorylation were markedly increased by acute exercise and declined to baseline during post-exercise recovery. Dnm1L expression was strongly associated with transcripts known to regulate mitochondrial metabolism and adaptations to exercise. Exercise increased the expression of DNM1L in skeletal muscle of healthy control and DG subjects, despite a 15% ↓(P = 0.01) in muscle DNM1L expression in DG at baseline. To interrogate the role of Dnm1L further, we exercise trained male mDrp1+/- mice and found that Drp1 deficiency reduced muscle endurance and running performance, and altered muscle adaptations in response to exercise training.ConclusionOur findings highlight the importance of mitochondrial dynamics, specifically Drp1 signaling, in the regulation of exercise performance and adaptations to endurance exercise training.

Published
2019

7. The Genetic Architecture of Diet‐Induced Hepatic Fibrosis in Mice

Author

Hui, Simon T, Kurt, Zeyneb, Tuominen, Iina, Norheim, Frode, C.Davis, Richard, Pan, Calvin, Dirks, Darwin L, Magyar, Clara E, French, Samuel W, Krishnan, Karthickeyan Chella, Sabir, Simon, Campos‐Pérez, Francisco, Méndez‐Sánchez, Nahum, Macías‐Kauffer, Luis, León‐Mimila, Paola, Canizales‐Quinteros, Samuel, Yang, Xia, Beaven, Simon W, Huertas‐Vazquez, Adriana, and Lusis, Aldons J

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Immunology, Human Genome, Hepatitis, Chronic Liver Disease and Cirrhosis, Digestive Diseases, Nutrition, Liver Disease, Genetics, 2.1 Biological and endogenous factors, Inflammatory and immune system, Amino Acids, Animals, Apolipoprotein E3, Cholesterol, Cholesterol Ester Transfer Proteins, Dietary Fats, Disease Models, Animal, Fatty Acids, Female, Gene Expression Profiling, Genome-Wide Association Study, Humans, Hyperlipidemias, Liver, Liver Cirrhosis, Male, Mice, Inbred C57BL, Mice, Transgenic, Non-alcoholic Fatty Liver Disease, Medical Biochemistry and Metabolomics, Gastroenterology & Hepatology, Clinical sciences
Abstract

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.

Published
2018

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

Author

Kurt, Zeyneb, Barrere-Cain, Rio, LaGuardia, Jonnby, Mehrabian, Margarete, Pan, Calvin, Hui, Simon T, Norheim, Frode, Zhou, Zhiqiang, Hasin, Yehudit, Lusis, Aldons J, and Yang, Xia

Subjects
Biochemistry and Cell Biology, Biological Sciences, Women's Health, Hepatitis, Digestive Diseases, Genetics, Health Disparities, Human Genome, Precision Medicine, Minority Health, Liver Disease, Chronic Liver Disease and Cirrhosis, Estrogen, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Inflammatory and immune system, Good Health and Well Being, Adipose Tissue, Animals, Castration, Female, Genomics, Lipid Metabolism, Liver, Male, Mice, Inbred C57BL, Non-alcoholic Fatty Liver Disease, Sex Characteristics, Signal Transduction, Transcriptome, Non-alcoholic fatty liver disease, Sexual dimorphism, Multi-omics integration, Key regulator genes, Bayesian networks, Coexpression networks, Hybrid mouse diversity panel
Abstract

BackgroundNon-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.ResultsWe 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.ConclusionsOur 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.

Published
2018

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

Author

Krishnan, Karthickeyan Chella, Kurt, Zeyneb, Barrere-Cain, Rio, Sabir, Simon, Das, Aditi, Floyd, Raquel, Vergnes, Laurent, Zhao, Yuqi, Che, Nam, Charugundla, Sarada, Qi, Hannah, Zhou, Zhiqiang, Meng, Yonghong, Pan, Calvin, Seldin, Marcus M, Norheim, Frode, Hui, Simon, Reue, Karen, Lusis, Aldons J, and Yang, Xia

Subjects
Biochemistry and Cell Biology, Biological Sciences, Chronic Liver Disease and Cirrhosis, Liver Disease, Genetics, Hepatitis, Digestive Diseases, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Animals, Databases, Genetic, Gene Expression Profiling, Gene Regulatory Networks, Genomics, HEK293 Cells, Humans, Insulin Resistance, Lipid Metabolism, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Mitochondria, Non-alcoholic Fatty Liver Disease, Obesity, Polymorphism, Single Nucleotide, Proteomics, Ribosomal Proteins, Transcriptome, glycolysis, integrative genomics, key driver genes, mitochondrial dysfunction, mouse diversity panel, multi-omics integration, network modeling, non-alcoholic fatty liver disease, oxidative phosphorylation, systems biology, Non-alcoholic fatty liver disease, multi-omics integration, network modeling, key drivers, mitochondrial dysfunction, oxidative phosphorylation, glycolysis, Biochemistry and cell biology
Abstract

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.

Published
2018

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

Author

Norheim, Frode, Bjellaas, Thomas, Hui, Simon T, Chella Krishnan, Karthickeyan, Lee, Jakleen, Gupta, Sonul, Pan, Calvin, Hasin-Brumshtein, Yehudit, Parks, Brian W, Li, Daniel Y, Bui, Hai H, Mosier, Marian, Wu, Yuping, Huertas-Vazquez, Adriana, Hazen, Stanley L, Gundersen, Thomas E, Mehrabian, Margarete, Tang, WH Wilson, Hevener, Andrea L, Drevon, Christian A, and Lusis, Aldons J

Subjects
Nutrition, Genetics, Digestive Diseases, Liver Disease, 2.1 Biological and endogenous factors, Aetiology, Animals, Ceramides, Diet, Female, Insulin Resistance, Liver, Male, Mice, Sex Characteristics, Testosterone, animal models, diabetes, lipidomics, mass spectrometry, sphingolipids, gonadectomy, sex hormones, genome-wide association studies, insulin resistance, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology
Abstract

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.

Published
2018

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

Author

Chella Krishnan, Karthickeyan, Kurt, Zeyneb, Barrere-Cain, Rio, Sabir, Simon, Das, Aditi, Floyd, Raquel, Vergnes, Laurent, Zhao, Yuqi, Che, Nam, Charugundla, Sarada, Qi, Hannah, Zhou, Zhiqiang, Meng, Yonghong, Pan, Calvin, Seldin, Marcus M, Norheim, Frode, Hui, Simon, Reue, Karen, Lusis, Aldons J, and Yang, Xia

Subjects
Liver, Mitochondria, Animals, Mice, Inbred Strains, Mice, Inbred C57BL, Humans, Mice, Insulin Resistance, Obesity, Ribosomal Proteins, Gene Expression Profiling, Proteomics, Genomics, Polymorphism, Single Nucleotide, Databases, Genetic, Male, Lipid Metabolism, Gene Regulatory Networks, HEK293 Cells, Transcriptome, Non-alcoholic Fatty Liver Disease, glycolysis, integrative genomics, key driver genes, mitochondrial dysfunction, mouse diversity panel, multi-omics integration, network modeling, non-alcoholic fatty liver disease, oxidative phosphorylation, systems biology, Chronic Liver Disease and Cirrhosis, Digestive Diseases, Liver Disease, Genetics, Hepatitis, Aetiology, 2.1 Biological and endogenous factors, Non-alcoholic fatty liver disease, multi-omics integration, network modeling, key drivers, mitochondrial dysfunction, oxidative phosphorylation, glycolysis, Biochemistry and Cell Biology
Abstract

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.

Published
2018

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

Author

Norheim, Frode, Hui, Simon, Kulahcioglu, Emre, Mehrabian, Margarete, Cantor, Rita, Pan, Calvin, Parks, Brian, and Lusis, Aldons

Subjects
genetics, gonadectomy, hormones, insulin, nonalcoholic fatty liver disease, nutrition/lipids, obesity, Animals, Diet, High-Fat, Fatty Liver, Female, Genome-Wide Association Study, Hormones, Hyperlipidemias, Insulin Resistance, Lipoproteins, HDL, Liver, Male, Mice, Non-alcoholic Fatty Liver Disease, Obesity, Polymorphism, Single Nucleotide, Sex Characteristics, Triglycerides
Abstract

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.

Published
2017

13. Genetic Architecture of Insulin Resistance in the Mouse

Author

Parks, Brian W, Sallam, Tamer, Mehrabian, Margarete, Psychogios, Nikolas, Hui, Simon T, Norheim, Frode, Castellani, Lawrence W, Rau, Christoph D, Pan, Calvin, Phun, Jennifer, Zhou, Zhenqi, Yang, Wen-Pin, Neuhaus, Isaac, Gargalovic, Peter S, Kirchgessner, Todd G, Graham, Mark, Lee, Richard, Tontonoz, Peter, Gerszten, Robert E, Hevener, Andrea L, and Lusis, Aldons J

Subjects
Biological Sciences, Genetics, Diabetes, Nutrition, Obesity, Human Genome, 2.1 Biological and endogenous factors, Metabolic and endocrine, 1-Acylglycerol-3-Phosphate O-Acyltransferase, Animals, Diet, High-Fat, Dietary Carbohydrates, Female, Genetic Variation, Genotype, Insulin Resistance, Male, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred DBA, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Endocrinology & Metabolism, Biochemistry and cell biology, Medical biochemistry and metabolomics
Abstract

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.

Published
2015

14. Avoiding 40% of the premature deaths in each country, 2010–30: review of national mortality trends to help quantify the UN Sustainable Development Goal for health

Author

Norheim, Ole F, Jha, Prabhat, Admasu, Kesetebirhan, Godal, Tore, Hum, Ryan J, Kruk, Margaret E, Gómez-Dantés, Octavio, Mathers, Colin D, Pan, Hongchao, Sepúlveda, Jaime, Suraweera, Wilson, Verguet, Stéphane, Woldemariam, Addis T, Yamey, Gavin, Jamison, Dean T, and Peto, Richard

Subjects
Pediatric, Behavioral and Social Science, Infection, Good Health and Well Being, Peace, Justice and Strong Institutions, Adolescent, Adult, Aged, Child, Child Mortality, Child, Preschool, Communicable Diseases, Conservation of Natural Resources, Female, Global Health, Goals, Humans, Infant, Infant Mortality, Infant, Newborn, Male, Maternal Mortality, Middle Aged, Mortality, Mortality, Premature, Nutrition Disorders, United Nations, Young Adult, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundThe UN will formulate ambitious Sustainable Development Goals for 2030, including one for health. Feasible goals with some quantifiable, measurable targets can influence governments. We propose, as a quatitative health target, "Avoid in each country 40% of premature deaths (under-70 deaths that would be seen in the 2030 population at 2010 death rates), and improve health care at all ages". Targeting overall mortality and improved health care ignores no modifiable cause of death, nor any cause of disability that is treatable (or also causes many deaths). 40% fewer premature deaths would be important in all countries, but implies very different priorities in different populations. Reinforcing this target for overall mortality in each country are four global subtargets for 2030: avoid two-thirds of child and maternal deaths; two-thirds of tuberculosis, HIV, and malaria deaths; a third of premature deaths from non-communicable diseases (NCDs); and a third of those from other causes (other communicable diseases, undernutrition, and injuries). These challenging subtargets would halve under-50 deaths, avoid a third of the (mainly NCD) deaths at ages 50-69 years, and so avoid 40% of under-70 deaths. To help assess feasibility, we review mortality rates and trends in the 25 most populous countries, in four country income groupings, and worldwide.MethodsUN sources yielded overall 1970-2010 mortality trends. WHO sources yielded cause-specific 2000-10 trends, standardised to country-specific 2030 populations; decreases per decade of 42% or 18% would yield 20-year reductions of two-thirds or a third.ResultsThroughout the world, except in countries where the effects of HIV or political disturbances predominated, mortality decreased substantially from 1970-2010, particularly in childhood. From 2000-10, under-70 age-standardised mortality rates decreased 19% (with the low-income and lower-middle-income countries having the greatest absolute gains). The proportional decreases per decade (2000-10) were: 34% at ages 0-4 years; 17% at ages 5-49 years; 15% at ages 50-69 years; 30% for communicable, perinatal, maternal, or nutritional causes; 14% for NCDs; and 13% for injuries (accident, suicide, or homicide).InterpretationModerate acceleration of the 2000-10 proportional decreases in mortality could be feasible, achieving the targeted 2030 disease-specific reductions of two-thirds or a third. If achieved, these reductions avoid about 10 million of the 20 million deaths at ages 0-49 years that would be seen in 2030 at 2010 death rates, and about 17 million of the 41 million such deaths at ages 0-69 years. Such changes could be achievable by 2030, or soon afterwards, at least in areas free of war, other major effects of political disruption, or a major new epidemic.FundingUK Medical Research Council, Norwegian Agency for Development Cooperation, Centre for Global Health Research, and Bill & Melinda Gates Foundation.

Published
2015

15. Evolocumab and clinical outcomes in patients with cardiovascular disease

Author

Sabatine, Marc S., Giugliano, Robert P., Keech, Anthony C., Honarpour, Narimon, Wiviott, Stephen D., Murphy, Sabina A., Kuder, Julia F., Wang, Huei, Liu, Thomas, Wasserman, Scott M., Sever, Peter S., Pedersen, Fish MP, Terje R., Abrahamsen, Te, Im, K, Kanevsky, E, Bonaca, Mp, Lira Pineda, A, Hanlon, K, Knusel, B, Somaratne, R, Kurtz, C, Scott, R, Accini Mendoza JL, Amerena, J, Badariene, J, Burgess, L, Ceska, R, Charng, Mj, Choi, D, Cobos, Jl, Dan, Ga, De Ferrari GM, Deedwania, Pc, Chopra, Vk, Erglis, A, Ezhov, Mv, Ferreira, J, Filipová, S, Gaciong, Za, Pasierski, T, Georgiev, Bg, Gonzalez-Galvez, G, Gouni-Berthold, I, Schäufele, T, Hirayama, A, Huber, K, Rammer, M, Kjaerulf Jensen, H, Wermuth, S, Jiang, L, Jukema, Jw, Kraydashenko, O, Leiter, La, Lewis, Bs, López-Miranda, J, Lorenzatti, Aj, Mach, F, Mcadam, B, Nilsson, L, Olsson, Å, Rallidis, L, Rogelio, Gg, Kerr Saraiva JF, Scheen, A, Schiele, F, Scott, Rs, Connolly, D, Siu, Cw, Tay, L, Thorgeirsson, G, Tikkanen, Mj, Tokgozoglu, Sl, Toth, K, Viigimaa, M, Wan Ahmad WA, Hennekens, Ch, Andreotti, F, Baigent, C, Brown, Wv, Davis, Br, Newcomer, Jw, Wood, Sk, Larosa, J, Ansell, B, Olsson, A, Lowe, C, Zahn, L, Awtry, E, Berger, C, Croce, K, Desai, A, Gelfand, E, Ho, C, Leeman, D, Link, M, Norden, A, Pande, A, Rost, N, Ruberg, F, Silverman, S, Singhal, A, Vita, J, Mackinnon, I, Vogel, Dr, Leon de la Fuente, R, Perna, E, Amuchastegui, M, Pacora, F, Hershson, A, Blumberg, E, Glenny, Ja, Colombo, H, Cuadrado, Ja, Nicolosi, L, Rojas, Cg, Ulla, Mr, Hasbani, Eg, Cuneo, C, Lopez Santi RG, Sanabria, Hd, Hrabar, A, Lozada, A, Begg, A, Lehman, S, Wittert, G, Juergens, C, Kostner, K, Beltrame, J, Simpson, R, Sinhal, A, Adams, M, Kritharides, L, Roberts Thomson, P, Cross, D, Thompson, P, Van Gaal, W, Cox, N, Farshid, A, Hammett, C, Garrahy, P, Prasan, A, Horrigan, M, Ebenbichler, C, Hanusch, U, Prager, R, Schernthaner, G, Luger, A, Siostrzonek, P, Toplak, H, Bergler-Klein, J, Paulweber, B, Sinzinger, H, Buysschaert, I, Thoeng, J, Vandekerckhove, H, Catez, E, Verheye, S, Descamps, O, Hoffer, E, Wollaert, B, Chenu, P, van de Borne, P, De Meulemeester, M, Friart, A, Charlier, F, De Raedt, H, Rietzschel, E, Roelandt, R, Lalmand, J, Tavares Russo LA, Reis, G, Duarte Barbosa EC, Vidotti, Mh, Fernandes Manenti ER, Dutra, O, Leaes, Pe, Rech, Rl, Bertolim Precoma, D, Nicolau, Jc, Amoedo, R, Eliaschewitz, Fg, Pereira, A, Kurtz Lisboa HR, Soares Piegas, L, Cunha Borges JL, Ferreira Rossi PR, Pimentel Filho, P, Bodanese, Lc, de Sa Cunha, R, Moura Jorge JC, Ardito, Wr, Barroso de Souza WK, Hissa, M, Izar, Mc, Manolova, A, Kitova, L, Kinova, E, Tzekova, M, Velchev, V, Tarnovska-Kadreva, R, Gotchev, D, Petrov, I, Raev, D, Trendafilova-Lazarova, D, Yotov, Y, Lazov, P, Rahimi, S, St Amour, E, Constance, C, Pesant, Y, Hess, A, Anderson, T, Sussex, B, Henein, S, Tsoukas, G, Pandey, As, Bergeron, J, Hart, R, Gosselin, G, Chehayeb, R, Hamet, P, Hartleib, M, Mukherjee, A, Halperin, F, Petrella, R, Bhargava, R, Lonn, E, Sabbah, E, Bata, I, Cha, J, Gaudet, D, Chapman, K, Murthy, D, Nigro, F, Rupka, D, Gossard, D, Gupta, M, Dowell, A, Mansour, S, Baass, A, Geadah, C, Huynh, T, Peterson, S, Poirier, P, Sabe-Affaki, G, Vertes, G, Crowley, D, Duchesne, L, Pincetti Jofre CP, Potthoff Cardenas, S, Conejeros Kindel, C, Saavedra Gajardo VA, Lanas Zanetti, F, Sepulveda Varela PA, Stockins Fernandez BA, Li, W, Li, D, Zhao, S, Li, Z, Wang, J, Yang, Y, Zhang, L, Yang, P, Zhang, X, Huang, H, Xue, L, Zheng, Z, Huang, W, Dai, H, Su, H, Zeng, X, Zheng, Y, Tang, Y, Yao, Z, Sun, Y, Du, Y, Ge, Z, Yan, J, Chen, X, Liu, F, Pei, H, Yang, X, Cui, H, Gu, Y, Yang, Z, Li, J, Lian, Y, Cui, Y, Wang, D, Jiang, J, Li, X, Chen, J, Mo, Z, Xu, P, He, Y, Zhou, C, Qu, P, Zhu, Y, Liu, Y, Shen, X, Gao, X, Terront Lozano MA, Moncada Corredor MA, Hernandez Triana, E, Botero Lopez, R, Coronel Arroyo JA, Quintero Baiz AE, Sanchez Vallejo, G, Arana Londoño, C, Molina de Salazar DI, Castellanos Bueno, R, Manzur Jattin, F, Cure Cure CA, Sotomayor Herazo, 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Tahirkheli, N, Delgado, E, Derian, W, Greenwald, J, Harris, M, Jackson, R, Marhefka, G, Mcelveen, W, Mooss, A, Morris, P, Murray, J, Pearlstein, P, Raisinghani, A, Rezkalla, S, Sakhrani, L, Schreibman, D, Shaoulian, E, Steinsapir, J, Yataco, A, De La Cruz, A, Fredrick, M, Goldenberg, E, Lee, D, Mccullum, K, Mclellan, B, Stephens, L, Wilson, S, Alfieri, A, Mandviwala, M, Orourke, D, Samal, A, Schmedtje, J, Waxman, F, Carhart, R, Clements, B, Dyke, C, Ghali, J, Gruberg, L, Hack, T, Jehle, A, Pogue, B, Schooley, C, and Shifrin, G

Subjects
Male, STATIN THERAPY, 2700 General Medicine, Disease, Cardiovascular, PLACEBO-CONTROLLED TRIAL, Gastroenterology, 0302 clinical medicine, Anticholesteremic Agent, Medicine, Myocardial infarction, 11 Medical and Health Sciences, ddc:616, Incidence, Antibodies, Monoclonal, General Medicine, Cholesterol, Cardiovascular Diseases, Monoclonal, Drug Therapy, Combination, Proprotein Convertase 9, Antibody, Aged, Anticholesteremic Agents, Atherosclerosis, Cholesterol, LDL, Double-Blind Method, Female, Follow-Up Studies, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Least-Squares Analysis, Middle Aged, Medicine (all), REDUCING LIPIDS, Human, medicine.medical_specialty, Evinacumab, Clinical Trials and Supportive Activities, PCSK9 INHIBITION, Follow-Up Studie, LDL, 03 medical and health sciences, Drug Therapy, Clinical Research, LDL-C, Least-Squares Analysi, Science & Technology, Unstable angina, PCSK9, medicine.disease, chemistry, Clinical Biochemistry, 030204 cardiovascular system & hematology, Bococizumab, FOURIER Steering Committee and Investigators, Medical and Health Sciences, chemistry.chemical_compound, Antibodies monoclonal, Cardiovascular Disease, 030212 general & internal medicine, Stroke, Humanized, RISK, biology, PCSK9 Inhibitors, 10051 Rheumatology Clinic and Institute of Physical Medicine, Heart Disease, Atherosclerosi, 6.1 Pharmaceuticals, Combination, Cardiology, Life Sciences & Biomedicine, Antibodies, Monoclonal, Humanized, EZETIMIBE, 610 Medicine & health, Antibodies, Medicine, General & Internal, General & Internal Medicine, Internal medicine, CORONARY-HEART-DISEASE, In patient, Heart Disease - Coronary Heart Disease, Alirocumab, Ldl cholesterol, business.industry, Evaluation of treatments and therapeutic interventions, Evolocumab, Good Health and Well Being, Settore MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, biology.protein, MODERATE, Hydroxymethylglutaryl-CoA Reductase Inhibitor, business
Abstract

Background Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. Methods We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. Results At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P

Published
2017

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