title: Precision-cut liver slices from diet-induced obese rats exposed to ethanol are susceptible to oxidative stress and increased fatty acid synthesis.
abstract: Oxidative stress from fat accumulation in the liver has many deleterious effects. Many believe that there is a second hit that causes relatively benign fat accumulation to transform into liver failure. Therefore, we evaluated the effects of ethanol on ex vivo precision-cut liver slice cultures (PCLS) from rats fed a high-fat diet resulting in fatty liver. Age-matched male Sprague-Dawley rats were fed either high-fat (obese) (45% calories from fat, 4.73 kcal/g) or control diet for 13 mo. PCLS were prepared, incubated with 25 mM ethanol for 24, 48, and 72 h, harvested, and evaluated for ethanol metabolism, triglyceride production, oxidative stress, and cytokine expression. Ethanol metabolism and acetaldehyde production decreased in PCLS from obese rats compared with age-matched controls (AMC). Increased triglyceride and smooth muscle actin production was observed in PCLS from obese rats compared with AMC, which further increased following ethanol incubation. Lipid peroxidation, measured by thiobarbituric acid reactive substances assay, increased in response to ethanol, whereas GSH and heme oxygenase I levels were decreased. TNF-α and IL-6 levels were increased in the PCLS from obese rats and increased further with ethanol incubation. Diet-induced fatty liver increases the susceptibility of the liver to toxins such as ethanol, possibly by the increased oxidative stress and cytokine production. These findings support the concept that the development of fatty liver sensitizes the liver to the effects of ethanol and leads to the start of liver failure, necrosis, and eventually cirrhosis.
authors.affiliation: Experimental Immunology Laboratory, Veterans Affairs Nebraska-Western Iowa Health Care System (VA NWIHCS), Omaha, Nebraska;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Duryee
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
authors.forename: Courtney S
authors.initials: CS
authors.lastname: Schaffert
authors.forename: Roger D
authors.initials: RD
authors.lastname: Reidelberger
authors.forename: Anand
authors.initials: A
authors.lastname: Dusad
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Anderson
authors.forename: Lynell W
authors.initials: LW
authors.lastname: Klassen
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Thiele
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D005227:Fatty Acids / Q000096:biosynthesis*; D005234:Fatty Liver / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D009765:Obesity / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol
keywords: alcohol liver disease; fatty liver disease; obesity; oxidative stress; precision-cut liver slices