Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease
Abstract 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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-10-01
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| Series: | Biology of Sex Differences |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13293-018-0205-7 |
| _version_ | 1818417520752721920 |
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| author | Zeyneb Kurt Rio Barrere-Cain Jonnby LaGuardia Margarete Mehrabian Calvin Pan Simon T Hui Frode Norheim Zhiqiang Zhou Yehudit Hasin Aldons J Lusis Xia Yang |
| author_facet | Zeyneb Kurt Rio Barrere-Cain Jonnby LaGuardia Margarete Mehrabian Calvin Pan Simon T Hui Frode Norheim Zhiqiang Zhou Yehudit Hasin Aldons J Lusis Xia Yang |
| author_sort | Zeyneb Kurt |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-14T12:08:06Z |
| format | Article |
| id | doaj.art-6774b51542b843a1b8717f6629c5094f |
| institution | Directory Open Access Journal |
| issn | 2042-6410 |
| language | English |
| last_indexed | 2024-12-14T12:08:06Z |
| publishDate | 2018-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Biology of Sex Differences |
| spelling | doaj.art-6774b51542b843a1b8717f6629c5094f2022-12-21T23:01:50ZengBMCBiology of Sex Differences2042-64102018-10-019111410.1186/s13293-018-0205-7Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver diseaseZeyneb Kurt0Rio Barrere-Cain1Jonnby LaGuardia2Margarete Mehrabian3Calvin Pan4Simon T Hui5Frode Norheim6Zhiqiang Zhou7Yehudit Hasin8Aldons J Lusis9Xia Yang10Department of Integrative Biology and Physiology, University of California, Los AngelesDepartment of Integrative Biology and Physiology, University of California, Los AngelesDepartment of Integrative Biology and Physiology, University of California, Los AngelesDepartment of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los AngelesDepartment of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los AngelesDepartment of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los AngelesDepartment of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los AngelesDepartment of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los AngelesDepartment of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los AngelesDepartment of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los AngelesDepartment of Integrative Biology and Physiology, University of California, Los AngelesAbstract 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.http://link.springer.com/article/10.1186/s13293-018-0205-7Non-alcoholic fatty liver disease (NAFLD)Sexual dimorphismMulti-omics integrationKey regulator genesBayesian networksCoexpression networks |
| spellingShingle | Zeyneb Kurt Rio Barrere-Cain Jonnby LaGuardia Margarete Mehrabian Calvin Pan Simon T Hui Frode Norheim Zhiqiang Zhou Yehudit Hasin Aldons J Lusis Xia Yang Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease Biology of Sex Differences Non-alcoholic fatty liver disease (NAFLD) Sexual dimorphism Multi-omics integration Key regulator genes Bayesian networks Coexpression networks |
| title | Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease |
| title_full | Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease |
| title_fullStr | Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease |
| title_full_unstemmed | Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease |
| title_short | Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease |
| title_sort | tissue specific pathways and networks underlying sexual dimorphism in non alcoholic fatty liver disease |
| topic | Non-alcoholic fatty liver disease (NAFLD) Sexual dimorphism Multi-omics integration Key regulator genes Bayesian networks Coexpression networks |
| url | http://link.springer.com/article/10.1186/s13293-018-0205-7 |
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