Abstract
The rise in prevalence of non-alcoholic fatty liver disease (NAFLD) constitutes an important public health concern worldwide. Including obesity, numerous risk factors of NAFLD such as benzo[a]pyrene (B[a]P) and ethanol have been identified as modifying the physicochemical properties of the plasma membrane in vitro thus causing membrane remodeling—changes in membrane fluidity and lipid-raft characteristics. In this study, the possible involvement of membrane remodeling in the in vivo progression of steatosis to a steatohepatitis-like state upon co-exposure to B[a]P and ethanol was tested in obese zebrafish larvae. Larvae bearing steatosis as the result of a high-fat diet were exposed to ethanol and/or B[a]P for seven days at low concentrations coherent with human exposure in order to elicit hepatotoxicity. In this condition, the toxicant co-exposure raised global membrane order with higher lipid-raft clustering in the plasma membrane of liver cells, as evaluated by staining with the fluoroprobe di-4-ANEPPDHQ. Involvement of this membrane’s remodeling was finally explored by using the lipid-raft disruptor pravastatin that counteracted the effects of toxicant co-exposure both on membrane remodeling and toxicity. Overall, it can be concluded that B[a]P/ethanol co-exposure can induce in vivo hepatotoxicity via membrane remodeling which could be considered as a good target mechanism for developing combination therapy to deal with steatohepatitis.
Highlights
The significant rise in obesity prevalence in recent decades constitutes an important public health concern worldwide
We found that liver steatosis could be induced in zebrafish larvae at 5 dpf, with only one day of high-fat diet (HFD) that increased oil red o staining, liver size with respect to whole body, triglyceride content, and mRNA level of apolipoprotein A-II (apoa2 and cyp2y3 gene—homologous of the human cytochrome P450 2E1 (CYP2E1) gene—in comparison to a standard diet (SD) [27]
HFD—the principal cause of steatosis—was identified as modifying the physicochemical properties of the membrane by altering its lipid composition or lipid-raft protein activity; it was proposed that this process was involved in non-alcoholic fatty liver disease (NAFLD) progression in association or not with hepatotoxicants [41,75,76]
Summary
The significant rise in obesity prevalence in recent decades constitutes an important public health concern worldwide. Steatosis dominates liver diseases in countries consuming the western diet, i.e., containing an important amount of fat and/or carbohydrates [2,3]. It is viewed as a benign hepatic lesion but can sensitize hepatocytes towards subsequent aggressions, thereby leading to steatohepatitis, which is characterized by liver cell death, inflammation and recurrent involvement of oxidative stress [4,5,6,7,8,9,10,11]. People with steatosis constitute a high-risk population for their evolution towards severe hepatic pathologies In this context, more thorough research, notably regarding the factors driving the pathological progression of steatosis to steatohepatitis, is urgently needed
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