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The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic Toll-like receptor expression in a mouse model of alcoholic liver disease
Open accessAbstract
BACKGROUND: Interactions between the gut, immune system, and the liver, as well as the type of fat in the diet, are critical components of alcoholic liver disease (ALD). The goal of the present study was to determine the effects of saturated fat (SF) and unsaturated fat (USF) on ethanol (EtOH)-induced gut-liver interactions in a mouse model of ALD. METHODS: C57BL/6N mice were fed Lieber-DeCarli liquid diets containing EtOH and enriched in USF (corn oil) or SF (medium chain triglycerides:beef tallow). Control mice were pair-fed on an isocaloric basis. Liver injury and steatosis, blood endotoxin levels, intestinal permeability, and tight junction (TJ) integrity, as well as hepatic Toll-like receptor (TLR) gene expression, were evaluated. RESULTS: After 8 weeks of EtOH feeding, liver injury and steatosis were observed in USF + EtOH group compared with control and SF + EtOH. Significantly increased intestinal permeability in conjunction with elevated blood endotoxin levels were observed in the ileal segments of the mice fed USF + EtOH. USF diet alone resulted in down-regulation of intestinal TJ protein mRNA expression compared with SF. Importantly, alcohol further suppressed TJ proteins in USF + EtOH, but did not affect intestinal TJ in SF + EtOH group. The type of fat in the diet alone did not affect hepatic TLR expression. Compared with control animals, hepatic TLR (TLR 1, 2, 3, 4, 7, 8, 9) mRNA expression was significantly (p < 0.05) increased in USF + EtOH, but not in SF + EtOH group. Notably, TLR5 was the only up-regulated TLR in both SF + EtOH and USF + EtOH groups. CONCLUSIONS: Dietary fat is an important cofactor in alcohol-associated liver injury. We demonstrate that USF (corn oil/linoleic acid) by itself results in dysregulation of intestinal TJ integrity leading to increased gut permeability, and alcohol further exacerbates these alterations. We postulate that elevated blood endotoxin levels in response to USF and alcohol in conjunction with up-regulation of hepatic TLRs combine to cause hepatic injury in ALD.
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“binge alcohol exposure [232], [233], [234], [235], [236], [237], [238], [239] and nonalcoholic substances including fructose [240], [241], [242] are known to promote gut leakiness, contributing to more severe inflammatory liver disease.”
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Metadata
- Authors
- Kirpich, I. A., Feng, W., Wang, Y., Liu, Y., Barker, D. F., Barve, S. S., & McClain, C. J.
- Affiliations
- University of Louisville (US)
- Corresponding author
- McClain, Craig J.
- ORCID
- Venue
- Alcoholism Clinical and Experimental Research
- Publisher
- Wiley
- Published
- 2011-12-07
- Volume
- 36
- Issue
- 5
- Pages
- 835-846
- ISSN
- 0145-6008 (ISSN-L)
- 1530-0277
- PMC
- PMC3319492
- OpenAlex
- W2098539191
- Cited by
- 135
- References
- 51
- Citations by year
- 2025: 11 · 2024: 6 · 2023: 7 · 2022: 12 · 2021: 10 · 2020: 8 · 2019: 8 · 2018: 8 · 2017: 18 · 2016: 11 · 2015: 11 · 2014: 10 · 2013: 11 · 2012: 4
- FWCI
- 5.61
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Alcoholism Clinical and Experimental Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Forest Service
- U.S. Public Health Service (R01 AAO14371)
- National Institute on Alcohol Abuse and Alcoholism (R01AA018016, R37AA010762, U01AA021901, R01AA010496, R21AA020849, P30AA019360, R01AA010762, R01AA015970, R01AA014371, P01AA017103, R01AA018869, R01 AA0015970, RC2AA019385)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK071765)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- alcoholic liver disease, dietary fat, saturated fat, unsaturated fat, medium-chain triglycerides, corn oil, ethanol, intestinal tight junctions, intestinal permeability, endotoxin, TLR5, liver injury, hepatic steatosis, gut-liver axis
- MeSH terms
- Ethanol, Animals, Body Composition, Body Weight, Dietary Fats, Unsaturated, Disease Models, Animal, Eating, Endotoxins, Liver, Liver Diseases, Alcoholic, Macrophages, Male, Mice, Inbred C57BL, Permeability, Up-Regulation, Oxidative Stress, Tight Junctions, Gastrointestinal Tract, Toll-Like Receptors, Mice
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