|Ronis, Martin - Arkansas Children'S Nutrition Research Center (ACNC)|
|Mercer, Kelly - Arkansas Children'S Nutrition Research Center (ACNC)|
|Suva, Larry - University Arkansas For Medical Sciences (UAMS)|
|Vantrease, Jamie - Arkansas Children'S Nutrition Research Center (ACNC)|
|Ferguson, Matthew - Arkansas Children'S Nutrition Research Center (ACNC)|
|Hogue, William - University Arkansas For Medical Sciences (UAMS)|
|Sharma, Neha - Arkansas Children'S Nutrition Research Center (ACNC)|
|Blackburn, Michael - Arkansas Children'S Nutrition Research Center (ACNC)|
|Badger, Thomas - Arkansas Children'S Nutrition Research Center (ACNC)|
Submitted to: Alcohol
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/16/2013
Publication Date: 5/1/2014
Citation: Ronis, M.J., Mercer, K., Suva, L.J., Vantrease, J., Ferguson, M.E., Hogue, W.R., Sharma, N., Blackburn, M., Badger, T.M. 2014. 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). Alcohol. 48(2):133-144.
Interpretive Summary: Health problems related to heavy drinking and alcoholism include weight loss and loss of body fat, liver injury sufficient to require transplant, and bone loss, increasing the long-term risk of osteoporosis. It is possible that these health effects are linked since alcohol effects on liver and bone are both associated with an inappropriate increase in fat in these tissues and this fat might originate from the fat lost from abdominal fat and from fat under the skin. However, responses to alcohol are very variable between people, and this may be linked to other diet components such as the level of fat or carbohydrate intake. In order to understand the interactions between fat-liver and bone after drinking alcohol and to examine the effects of diet on this process, we treated male rats with alcohol in liquid diets made with either low or high levels of simple carbohydrates or fat using a feeding tube to equalize the level of calories and examined the effects on fat, liver, and bone. Alcohol treatment resulted in fat and bone loss in both diets, and unlike some other reports we did not observe deceases in blood levels of the fat-associated hormone adiponectin. However, alcohol treatment had dramatically different effects on development of liver injury depending on dietary ratios of fat to carbohydrate. In the presence of high carbohydrate diet alcohol produced rapid increases in liver fat, but over time the livers of rats fed high carbohydrate diets without alcohol became equally fatty and there was little evidence of alcohol-specific liver pathology. Increased liver fat was associated with increased synthesis of fatty acids in the liver and with activation of a transcription factor ChREBP in both high carbohydrate controls and alcohol-high fat treated rats. These data suggest alcohol and sugars produce fatty liver by the same mechanism and that alcoholic and nonalcoholic liver disease in patients consuming high levels of dietary carbohydrate are essentially indistinguishable. In contrast, when given with high fat diets, alcohol treatment resulted in less liver fat accumulation but more alcohol-specific liver injury. These results suggest that interactions between diet composition and alcohol are complex, tissue specific, and dependent on the length of exposure. Diet is an important influence in development of alcoholic fatty liver injury. Importantly, it appears that diet composition does not affect alcohol-associated skeletal toxicity.
Technical Abstract: Alcohol abuse is associated with the development of fatty liver disease and also with significant bone loss in both genders. In this study, we examined ethanol (EtOH)-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 EtOH (13 g/kg/d). After 14, 28, or 67 d, liver and bone were harvested and analyzed. HC rats gained more weight and had larger fat pads than HF rats with or without EtOH. Steatosis developed in HC+EtOH compared to 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 Sirt-1 or nuclear sterol regulatory binding element protein (SREBP-1c). EtOH reduced serum leptin (P< 0.05) but not adiponectin. Over time, HC rats developed fatty liver independent of EtOH. FA degradation was significantly elevated by EtOH in both HC and HF groups (P<0.05). HF+EtOH rats had increased oxidative stress from 28 d, 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 d 67, with no observed increase in necrosis. Unlike liver pathology, no dietary differences were observed on EtOH-induced bone loss 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.