한빛사논문
- 조회1,458
Young-Eun Cho#1,2, Do-Kyun Kim#3, Wonhyo Seo4, Bin Gao4, Seong-Ho Yoo5, and Byoung-Joon Song1*
1 Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA,
2 Department of Food and Nutrition, Andong National University, Andong, Kyungpook, South Korea,
3 Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1881, USA,
4 Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA,
5 Department of Forensic Medicine, Seoul National University College of Medicine, Seoul, South Korea.
#These authors equally contributed for the report.
*To whom correspondence should be addressed: Dr. B. J. Song, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892-9410, USA.
Abstract
Fructose intake is known to induce obesity, insulin resistance, metabolic syndrome and non‐alcoholic fatty liver disease (NAFLD). We aimed to evaluate the effects of fructose drinking on gut leakiness, endotoxemia, and NAFLD and study the underlying mechanisms in rats, mice, and T84 colon cells. The levels of ileum junctional proteins, oxidative stress markers and apoptosis‐related proteins in rodents, T84 colonic cells and human ileums were determined by immunoblot, immunoprecipitation, and immunofluorescence analyses. Fructose drinking caused microbiome change, leaky gut, and hepatic inflammation/fibrosis with increased levels of nitroxidative stress marker proteins cytochrome P450‐2E1 (CYP2E1), inducible nitric oxide synthase, and nitrated proteins in small intestine and liver of rodents. Fructose drinking significantly elevated plasma bacterial endotoxin levels likely resulting from decreased levels of intestinal tight junction (TJ) proteins (ZO‐1, occludin, claudin‐1, and claudin‐4), adherent junction (AJ) proteins (β‐catenin and E‐cadherin), and desmosome plakoglobin along with α‐tubulin in wild‐type rodents but not in the fructose‐exposed Cyp2e1‐null mice. Consistently, decreased intestinal TJ/AJ proteins and increased hepatic inflammation with fibrosis were observed in autopsied obese people compared to lean individuals. Furthermore, histological and biochemical analyses showed markedly elevated hepatic fibrosis markers proteins in fructose‐exposed rats compared to controls. Immunoprecipitation followed by immunoblot analyses revealed that intestinal TJ proteins were nitrated and ubiquitinated, leading to their decreased levels in the fructose‐exposed rats.
Conclusion: These results showed for the first time that fructose intake causes protein nitration of intestinal TJ and AJ proteins, resulting in increased gut leakiness, endotoxemia and steatohepatitis with liver fibrosis in a CYP2E1-dependent manner.
Keywords : fructose drinking, leaky gut, endotoxemia, nonalcoholic steatohepatitis, CYP2E1, oxidative and nitrative stress
논문정보
- Research article
- 2019년 04월 (BRIC 등록일 2019-04-16)
- 국내+국외 연구진
- 생명과학 > 영양학
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