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Review
. 2022 Jan 19;23(3):1062.
doi: 10.3390/ijms23031062.

Xenobiotic-Induced Aggravation of Metabolic-Associated Fatty Liver Disease

Julie Massart  1 , Karima Begriche  1 , Anne Corlu  1 , Bernard Fromenty  1
Affiliations
Review

Xenobiotic-Induced Aggravation of Metabolic-Associated Fatty Liver Disease

Julie Massart et al. Int J Mol Sci. .

Abstract

Metabolic-associated fatty liver disease (MAFLD), which is often linked to obesity, encompasses a large spectrum of hepatic lesions, including simple fatty liver, steatohepatitis, cirrhosis and hepatocellular carcinoma. Besides nutritional and genetic factors, different xenobiotics such as pharmaceuticals and environmental toxicants are suspected to aggravate MAFLD in obese individuals. More specifically, pre-existing fatty liver or steatohepatitis may worsen, or fatty liver may progress faster to steatohepatitis in treated patients, or exposed individuals. The mechanisms whereby xenobiotics can aggravate MAFLD are still poorly understood and are currently under deep investigations. Nevertheless, previous studies pointed to the role of different metabolic pathways and cellular events such as activation of de novo lipogenesis and mitochondrial dysfunction, mostly associated with reactive oxygen species overproduction. This review presents the available data gathered with some prototypic compounds with a focus on corticosteroids and rosiglitazone for pharmaceuticals as well as bisphenol A and perfluorooctanoic acid for endocrine disruptors. Although not typically considered as a xenobiotic, ethanol is also discussed because its abuse has dire consequences on obese liver.

Keywords: NASH; drugs; endocrine disruptors; environmental contaminants; ethanol; fatty liver; obesity.

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Conflict of interest statement

J. Massart, K. Begriche, A. Corlu and B. Fromenty declare that they have no conflict of interest in relation to this work.

Figures

Figure 1
Figure 1
Mechanisms whereby xenobiotics can aggravate obesity-related fatty liver. Xenobiotics can exacerbate pre-existent lipid accumulation in hepatocytes by direct mechanisms such as stimulation of de novo lipogenesis (DNL), increased non-esterified fatty acid (NEFA) uptake, reduction in fatty acid oxidation and impairment of very low-density lipoprotein (VLDL) secretion. Stimulation of DNL results from the activation of different lipogenic nuclear receptors such as PPARγ and PXR. Alternatively, increased DNL is secondary to insulin resistance, for instance, at the level of skeletal muscle and adipose tissue. Insulin resistance leads to hyperinsulinemia, which activates SREBP1c in hepatocytes. Insulin resistance in white adipose tissue also favors triacylglycerol lipolysis, thus leading to the unrestrained release in blood of NEFAs freely entering the liver via FAT/CD36 or other fatty acid transporters. If insulin resistance progresses to type 2 diabetes, hyperglycemia increases hepatic DNL via the activation of ChREBP. Reduced fatty acid oxidation can be attributed to different mechanisms, including reduced PPARα activity, or direct impairment of mitochondrial enzymes. Reduced VLDL secretion can be secondary to endoplasmic reticulum stress. Finally, impairment of autophagy favors lipid accumulation by reducing the clearance of excessive lipid droplets. Some connection arrows are not mentioned for the sake of clarity. Further information is provided in the text.
Figure 2
Figure 2
Mechanisms whereby xenobiotics can favor the progression of obesity-related fatty liver to NASH, characterized by necroinflammation, hepatocyte ballooning, apoptosis and fibrosis, in addition to steatosis. Mitochondrial dysfunction, in particular at the level of the respiratory chain, leads to reactive oxygen species (ROS) overproduction, which, in turn, induces oxidative stress. Mitochondrial dysfunction, ROS overproduction and oxidative stress trigger cell death by necrosis or apoptosis. Cell death can also be induced by different cytokines such as TNF-αand Fas ligand. ROS overproduction and hepatocyte cell death favor inflammation and fibrosis through the activation of Kupffer cells and stellate cells, respectively. Finally, endoplasmic reticulum (ER) stress can also lead to cell death and oxidative stress (not shown). Note that there is an interplay between mitochondrial dysfunction and ER stress. Some connection arrows are not mentioned for the sake of clarity. Further information is provided in the text.
Figure 3
Figure 3
Potential mechanisms involved in PFOA-induced hepatic steatosis. PFAO can directly bind PPARγ or activate PXR, both transcription factors inducing the expression of genes involved in fatty acid uptake and de novo lipogenesis. PFOA reduces the expression and activity of HNF4α, leading to alteration in fatty acid oxidation and very low-density lipoprotein (VLDL) secretion. Reduced VLDL secretion can be secondary to endoplasmic reticulum stress caused by PFOA. Reduction in autophagy by PFOA favors lipid accumulation by reducing the clearance of excessive lipid droplets. Finally, PFOA reduces adiposity, which contributes to an increased lipid flux to the liver in the context of obesity. (formula image: increase; formula image: decrease).
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References

    1. Eslam M., Sanyal A.J., George J., Sanyal A., Neuschwander-Tetri B., Tiribelli C., Kleiner D.E., Brunt E., Bugianesi E., Yki-Järvinen H., et al. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology. 2020;158:1999–2014.e1. doi: 10.1053/j.gastro.2019.11.312. - DOI - PubMed
    1. Tschöp M.H., Finan B., Clemmensen C., Gelfanov V., Perez-Tilve D., Müller T.D., DiMarchi R.D. Unimolecular Polypharmacy for Treatment of Diabetes and Obesity. Cell Metab. 2016;24:51–62. doi: 10.1016/j.cmet.2016.06.021. - DOI - PubMed
    1. Assari S., Wisseh C., Bazargan M. Obesity and Polypharmacy among African American Older Adults: Gender as the Moderator and Multimorbidity as the Mediator. Int. J. Environ. Res. Public. Health. 2019;16:2181. doi: 10.3390/ijerph16122181. - DOI - PMC - PubMed
    1. Joshi-Barve S., Kirpich I., Cave M.C., Marsano L.S., McClain C.J. Alcoholic, Nonalcoholic, and Toxicant-Associated Steatohepatitis: Mechanistic Similarities and Differences. Cell. Mol. Gastroenterol. Hepatol. 2015;1:356–367. doi: 10.1016/j.jcmgh.2015.05.006. - DOI - PMC - PubMed
    1. Yeh M.M., Brunt E.M. Pathological Features of Fatty Liver Disease. Gastroenterology. 2014;147:754–764. doi: 10.1053/j.gastro.2014.07.056. - DOI - PubMed

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