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.

Dietary Macronutrient Composition Determines the Contribution of DGAT1 to Alcoholic Steatosis

“…Liangpunsakul and colleagues (2013) found increased nuclear localization of ChREBP in alcohol‐fed mice consuming a low‐fat, liquid diet signals an increase in de novo lipogenesis via FAS and ACC. This is similar to data from Ronis and colleagues () who reported a similar finding in rats fed alcohol intragastrically. Our analysis of Chrebp mRNA levels revealed increased expression in the livers of mice consuming a high‐fat diet, although we did not observe any significant changes in the expression of Fasn or Acc (data not shown).…”

“…Our analysis of Chrebp mRNA levels revealed increased expression in the livers of mice consuming a high‐fat diet, although we did not observe any significant changes in the expression of Fasn or Acc (data not shown). This result is similar to that observed by Ronis and colleagues () who reported higher ChREBP expression in rats consuming a high‐fat diet, albeit we did not observe a significant alcohol effect. Interestingly, our results for Srebf1 expression closely match Ronis and colleagues (), such that they observed decreased expression in response to alcohol and higher dietary fat content.…”

“…This result is similar to that observed by Ronis and colleagues () who reported higher ChREBP expression in rats consuming a high‐fat diet, albeit we did not observe a significant alcohol effect. Interestingly, our results for Srebf1 expression closely match Ronis and colleagues (), such that they observed decreased expression in response to alcohol and higher dietary fat content. Moreover, these results are consistent with another study showing decreased Srebf1 expression and no corresponding change in Fasn expression (You et al., ).…”

Increased 4-hydroxynonenal protein adducts in male GSTA4–4/PPAR-α double knockout mice enhance injury during early stages of alcoholic liver disease

“…Malonyl-CoA is both a FA precursor and an allosteric inhibitor of FA uptake into mitochondria, the net effect of which is to increase hepatic FA concentrations. EtOH has been shown to both increase FA transport into hepatocytes and to stimulate FA synthesis via activation of the transcription factors SREBP-1c and ChREBP (31,36,44). Increased steatosis in EtOH GSTA4Ϫ/Ϫ mice is consistent with additive effects of these previously described mechanisms.…”

Liver steatosis in hepatitis C patients

“…Another transcription factor involved in liver steatosis is carbohydrate response element binding protein (ChREBP), whose activity is induced by a high carbohydrate diet, insulin [37] and ethanol [38] . It increases the expression of both lipogenic enzymes (such as fatty acid synthase) and glycolytic ones [39] .…”