Alcoholic vs non-alcoholic fatty liver in rats: distinct differences in endocytosis and vesicle trafficking despite similar pathology

Abstract

BackgroundNon-alcoholic and alcoholic fatty liver disease (NAFLD and AFLD, respectively) are major health problems, as patients with either condition can progress to hepatitis, fibrosis, and cirrhosis. Although histologically similar, key differences likely exist in these two models. For example, altered content of several vesicle trafficking proteins have been identified in AFLD, but their content in NAFLD is unknown. In this study, we compared select parameters in NAFLD and AFLD in a rat model.MethodsWe fed either Lieber- DeCarli liquid control or alcohol-containing (35 % as calories) diet (AFLD model) or lean or high-fat (12 or 60 % derived from fat, respectively) pellets (NAFLD model) for 8–10 weeks, n = 8 in each model. Serum, hepatocytes and liver tissue were analyzed. Liver injury markers were measured in serum, triglyceride content and endocytosis (binding and internalization of 125I- asialoorosomucoid) was measured in isolated hepatocytes, and content of selected trafficking proteins (Rab3D, Rab7 and Rab18) were determined in whole liver tissue.ResultsAlthough liver injury markers and triglyceride content were similar in both models, binding and internalization of 125I- asialoorosomucoid was significantly impaired in the hepatocytes from AFLD, but not NAFLD, animals. In addition, protein content of the asialoglycoprotein receptor (ASGPR) and three trafficking proteins, Rab3D, Rab7and Rab18, were significantly decreased after alcohol, but not high-fat feeding. Levels of protein carbonylation, amount of glutathione stores, and lipid peroxidation were similar irrespective of the insult to the livers that resulted in fatty liver.ConclusionImpairments in protein trafficking in AFLD are likely a direct result of alcohol administration, and not a function of fatty liver.

Dysregulation of Bile Acids in Patients with NAFLD

“…Serum total bile acid concentrations were markedly elevated by sevenfold from 1.9 ± 1.0 μM in wt control mice to 14.9 ± 5.4 μM in ob/ob mice [118]. In contrast to the findings from the studies described above, a more recent study showed that total serum bile acid concentrations were not significantly different in HFD-induced NAFLD mice than mice on control diet [119].…”

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

“…Like NAFLD, the prevalence of AFLD is expected to rise (Toshikuni et al 2014). While both AFLD and NAFLD have similar histology and disease progression, AFLD also induces molecular and clinical changes that are attributed to high alcohol consumption, and not as a result of hepatic lipid accumulation (Toshikuni et al 2014, Rasineni et al 2016. Interestingly, both AFLD and NAFLD are strongly associated with metabolic syndrome and type 2 diabetes (Kotronen et al 2010), suggesting that fatty liver, independent of origin, promotes systemic metabolic dysfunction.…”

A Panel of Protein Kinase Chemosensors Distinguishes Different Types of Fatty Liver Disease

“…For the NAFLD model, simple steatosis was generated by feeding 200 g male Wistar rats with a high-fat diet consisting of 60% calories from saturated, monounsaturated, and polyunsaturated fatty acids (ResearchDiets, D08060104) ad libitum for 8 weeks. 5 To generate their respective controls, rats of the same age and weight were fed a control diet consisting of 10% calories from fatty acids (Research Diets, D12450K) ad libitum for 8 weeks. For the AFLD model, male Wistar rats were pair-fed with Lieber− DeCarli control or EtOH−liquid diets that contained calories of 18% from protein, 35% from fat, 11% from carbohydrate, and 36% from ethanol.…”

“…For the AFLD model, male Wistar rats were pair-fed with Lieber− DeCarli control or EtOH−liquid diets that contained calories of 18% from protein, 35% from fat, 11% from carbohydrate, and 36% from ethanol. 5 In the control diet, ethanol was replaced isocalorically with maltodextrin.…”