17‐Beta Hydroxysteroid Dehydrogenase 13 Deficiency Does Not Protect Mice From Obesogenic Diet Injury
العنوان: | 17‐Beta Hydroxysteroid Dehydrogenase 13 Deficiency Does Not Protect Mice From Obesogenic Diet Injury |
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المؤلفون: | Bin Gao, Joselyn N. Allen, Natalia Y. Kedishvili, Philip M. Brown, Dennis D. Lin, Maren C. Podszun, Regina Umarova, Dechun Feng, Olga V. Belyaeva, Yanling Ma, Jason Roszik, David E. Kleiner, Oksana Gavrilova, Yaron Rotman, Jing Ma |
المصدر: | Hepatology |
بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2021. |
سنة النشر: | 2021 |
مصطلحات موضوعية: | Male, 0301 basic medicine, medicine.medical_specialty, Cirrhosis, 17-Hydroxysteroid Dehydrogenases, Diet, High-Fat, Weight Gain, Article, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Fibrosis, Internal medicine, Lipid droplet, Nonalcoholic fatty liver disease, Animals, Medicine, Hydroxysteroid dehydrogenase, Mice, Knockout, Liver injury, Ethanol, Hepatology, business.industry, Cholesterol, medicine.disease, Lipids, Fatty Liver, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Liver, chemistry, Diet, Western, 030211 gastroenterology & hepatology, Steatosis, business |
الوصف: | Background and aims 17-Beta hydroxysteroid dehydrogenase 13 (HSD17B13) is genetically associated with human nonalcoholic fatty liver disease (NAFLD). Inactivating mutations in HSD17B13 protect humans from NAFLD-associated and alcohol-associated liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma, leading to clinical trials of anti-HSD17B13 therapeutic agents in humans. We aimed to study the in vivo function of HSD17B13 using a mouse model. Approach and results Single-cell RNA-sequencing and quantitative RT-PCR data revealed that hepatocytes are the main HSD17B13-expressing cells in mice and humans. We compared Hsd17b13 whole-body knockout (KO) mice and wild-type (WT) littermate controls fed regular chow (RC), a high-fat diet (HFD), a Western diet (WD), or the National Institute on Alcohol Abuse and Alcoholism model of alcohol exposure. HFD and WD induced significant weight gain, hepatic steatosis, and inflammation. However, there was no difference between genotypes with regard to body weight, liver weight, hepatic triglycerides (TG), histological inflammatory scores, expression of inflammation-related and fibrosis-related genes, and hepatic retinoid levels. Compared to WT, KO mice on the HFD had hepatic enrichment of most cholesterol esters, monoglycerides, and certain sphingolipid species. Extended feeding with the WD for 10 months led to extensive liver injury, fibrosis, and hepatocellular carcinoma, with no difference between genotypes. Under alcohol exposure, KO and WT mice showed similar hepatic TG and liver enzyme levels. Interestingly, chow-fed KO mice showed significantly higher body and liver weights compared to WT mice, while KO mice on obesogenic diets had a shift toward larger lipid droplets. Conclusions Extensive evaluation of Hsd17b13 deficiency in mice under several fatty liver-inducing dietary conditions did not reproduce the protective role of HSD17B13 loss-of-function mutants in human NAFLD. Moreover, mouse Hsd17b13 deficiency induces weight gain under RC. It is crucial to understand interspecies differences prior to leveraging HSD17B13 therapies. |
تدمد: | 1527-3350 0270-9139 |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::36ba83a588bfcd957f52f9187bd5da7e https://doi.org/10.1002/hep.31517 |
حقوق: | OPEN |
رقم الأكسشن: | edsair.doi.dedup.....36ba83a588bfcd957f52f9187bd5da7e |
قاعدة البيانات: | OpenAIRE |
تدمد: | 15273350 02709139 |
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