title: Influence of fat/carbohydrate ratio on progression of fatty liver disease and on development of osteopenia in male rats fed alcohol via total enteral nutrition (TEN).
abstract: Alcohol abuse is associated with the development of fatty liver disease and also with significant osteopenia in both genders. In this study, we examined ethanol-induced pathology in response to diets with differing fat/carbohydrate ratios. Male Sprague-Dawley rats were fed intragastrically with isocaloric liquid diets. Dietary fat content was either 5% (high carbohydrate, HC) or 45% (high fat, HF), with or without ethanol (12-13 g/kg/day). After 14, 28, or 65 days, livers were harvested and analyzed. In addition, bone morphology was analyzed after 65 days. HC rats gained more weight and had larger fat pads than HF rats with or without ethanol. Steatosis developed in HC + ethanol (HC + EtOH) compared to HF + ethanol (HF + EtOH) rats, accompanied by increased fatty acid (FA) synthesis and increased nuclear carbohydrate response element binding protein (ChREBP) (p < 0.05), but in the absence of effects on hepatic silent mating type information regulation 2 homolog (SIRT-1) or nuclear sterol regulatory binding element protein (SREBP-1c). Ethanol reduced serum leptin (p < 0.05) but not adiponectin. Over time, HC rats developed fatty liver independent of ethanol. FA degradation was significantly elevated by ethanol in both HC and HF groups (p < 0.05). HF + EtOH rats had increased oxidative stress from 28 days, increased necrosis compared to HF controls and higher expression of cytochromes P450, CYP2E1, and CYP4A1 compared to HC + EtOH rats (p < 0.05). In contrast, HC + EtOH rats had no significant increase in oxidative stress until day 65 with no observed increase in necrosis. Unlike liver pathology, no dietary differences were observed on ethanol-induced osteopenia in HC compared to HF groups. These data demonstrate that interactions between diet composition and alcohol are complex, dependent on the length of exposure, and are an important influence in development of fatty liver injury. Importantly, it appears that diet composition does not affect alcohol-associated skeletal toxicity.
authors.affiliation: Arkansas Children's Nutrition Center, Little Rock, AR, USA; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address: RonisMartinJ@uams.edu.
authors.forename: Martin J J
authors.initials: MJ
authors.lastname: Ronis
authors.affiliation: Arkansas Children's Nutrition Center, Little Rock, AR, USA; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Mercer
authors.affiliation: Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Suva
authors.affiliation: Arkansas Children's Nutrition Center, Little Rock, AR, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Vantrease
authors.affiliation: Arkansas Children's Nutrition Center, Little Rock, AR, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ferguson
authors.affiliation: Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Hogue
authors.affiliation: Arkansas Children's Nutrition Center, Little Rock, AR, USA.
authors.forename: Neha
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Arkansas Children's Nutrition Center, Little Rock, AR, USA; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Cleves
authors.affiliation: Arkansas Children's Nutrition Center, Little Rock, AR, USA; Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Blackburn
authors.affiliation: Arkansas Children's Nutrition Center, Little Rock, AR, USA; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Badger
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D001851:Bone Diseases, Metabolic / Q000209:etiology*; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D042926:Cytochrome P-450 CYP4A / Q000096:biosynthesis; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D059305:Diet, High-Fat / Q000009:adverse effects; D004040:Dietary Carbohydrates / Q000008:administration & dosage*; D004041:Dietary Fats / Q000008:administration & dosage*; D018450:Disease Progression; D004750:Enteral Nutrition; D000431:Ethanol / Q000008:administration & dosage; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced*; D008108:Liver Diseases, Alcoholic / Q000209:etiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004040:Dietary Carbohydrates; D004041:Dietary Fats; D005227:Fatty Acids; C442825:Mlxipl protein, rat; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D042926:Cytochrome P-450 CYP4A
keywords: Alcohol; Bone; Carbohydrate; Diet; Ethanol; Fatty acid synthesis; Fatty liver disease; Liver; Polyunsaturated fat; Steatosis