Why Hepatic CYP2E1-Elevation by Itself Is Insufficient for Inciting NAFLD/NASH: Inferences from Two Genetic Knockout Mouse Models.

Maria Almira Correia,Doyoung Kwon

doi:10.3390/biology9120419

Maria Almira Correia, Doyoung Kwon

Open Access

https://doi.org/10.3390/biology9120419

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Journal: Biology	Publication Date: Nov 26, 2020
Citations: 14	License type: CC BY 4.0

Affiliation: University of California, San Francisco

Abstract

Simple SummaryCytochrome P450 CYP2E1 is an enzyme engaged in the breakdown of various compounds (drugs, carcinogens, dietary nutrients and toxins) as well as endogenous compounds (steroids and fatty acids), resulting in both detoxification and elimination of these agents. Often, it can also convert these agents, i.e., Acetaminophen, into more toxic products. Elevated liver CYP2E1 content is implicated in various metabolic diseases including alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), diabetes and obesity. While liver CYP2E1 elevation is considered essential to the pathogenesis of these liver diseases, our findings of elevated liver CYP2E1 content in two genetic mouse models with impaired degradation and thus a disrupted disposal of CYP2E1 when fed a regular lab chow diet, argue that it is not sufficient for triggering NAFLD/NASH. Thus, despite comparable hepatic CYP2E1 elevation and functional stabilization in these two models, NAFLD/NASH was only observed in the mouse livers that exhibited concurrently enhanced liver fat production. These findings reinforce the notion that in addition to elevated liver CYP2E1 content, CYP2E1-mediated NAFLD/NASH requires liver fat accumulation derived from either enhanced liver fat-production or ingestion of a high fat/high carbohydrate diet.Hepatic cytochrome P450 CYP2E1 is an enzyme engaged in the metabolic biotransformation of various xenobiotics and endobiotics, resulting in both detoxification and/or metabolic activation of its substrates to more therapeutic or toxic products. Elevated hepatic CYP2E1 content is implicated in various metabolic diseases including alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), diabetes and obesity. While hepatic CYP2E1 elevation is considered essential to the pathogenesis of these liver diseases, our findings in two mouse models of E3 ubiquitin ligase genetic ablation fed a regular lab chow diet, argue that it is not sufficient for triggering NAFLD/NASH. Thus, albeit comparable hepatic CYP2E1 elevation and functional stabilization in these two models upon E3 ubiquitin ligase genetic ablation and consequent disruption of its ubiquitin-dependent proteasomal degradation, NAFLD/NASH was only observed in the mouse livers that exhibited concurrent SREBP1c-transcriptional upregulation of hepatic lipogenesis. These findings reinforce the critical complicity of an associated prolipogenic scenario induced by either an inherently upregulated hepatic lipogenesis or a high fat/high carbohydrate diet in CYP2E1-mediated NAFLD/NASH.

Highlights

Human liver CYP2E1 is an endoplasmic reticulum (ER)-anchored cytochrome P450 involved in the biotransformation of clinically relevant drugs, ethanol and other xenobiotics, carcinogens, endogenous acetone and fatty acids to toxic/reactive intermediates [1,2,3,4]
In obese and/or Type II diabetic humans as well as dietary non-alcoholic fatty liver disease (NAFLD) rodent models, such CYP2E1 overexpression has been invariably linked to insulin resistance and the progression of NAFLD to nonalcoholic steatohepatitis (NASH) [10,12,13,14]
We examined whether a comparable hepatic CYP2E1 stabilization observed upon liver-specific genetic ablation of gp78/AMFR, an ER-polytopic E3 Ub-ligase known to participate in CYP2E1-Ub-dependent proteasomal degradation (UPD) [30,33], would mimic the findings in C-terminus of Hsc70-interacting protein (CHIP)−/− -mice [29]

Summary

Introduction

Human liver CYP2E1 is an endoplasmic reticulum (ER)-anchored cytochrome P450 involved in the biotransformation of clinically relevant drugs (acetaminophen, halothane), ethanol and other xenobiotics, carcinogens (nitrosamines), endogenous acetone and fatty acids (arachidonic acid) to toxic/reactive intermediates [1,2,3,4]. JNK-cascade and microvesicular fat accumulation quite early at 2 months, which within 8–9 months of age progressed to macrovesicular fat accumulation, hepatocyte ballooning and injury, typical of clinical NASH [29] This occurred in spite of the fact that these CHIP−/− -mice had been fed a regular, non-fat/carbohydrate-enriched chow-diet, suggesting that overexpression of hepatic CYP2E1 content and consequent oxidative stress were sufficient for NASH-development [29].

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