Endocrine-disrupting chemicals and fatty liver disease

Abstract

A growing epidemic of nonalcoholic fatty liver disease (NAFLD) is paralleling the increase in the incidence of obesity and diabetes mellitus in countries that consume a Western diet. As NAFLD can lead to life-threatening conditions such as cirrhosis and hepatocellular carcinoma, an understanding of the factors that trigger its development and pathological progression is needed. Although by definition this disease is not associated with alcohol consumption, exposure to environmental agents that have been linked to other diseases might have a role in the development of NAFLD. Here, we focus on one class of these agents, endocrine-disrupting chemicals (EDCs), and their potential to influence the initiation and progression of a cascade of pathological conditions associated with hepatic steatosis (fatty liver). Experimental studies have revealed several potential mechanisms by which EDC exposure might contribute to disease pathogenesis, including the modulation of nuclear hormone receptor function and the alteration of the epigenome. However, many questions remain to be addressed about the causal link between acute and chronic EDC exposure and the development of NAFLD in humans. Future studies that address these questions hold promise not only for understanding the linkage between EDC exposure and liver disease but also for elucidating the molecular mechanisms that underpin NAFLD, which in turn could facilitate the development of new prevention and treatment opportunities.

Figure 1. Pathophysiology of NAFLD progression

From left to right: a healthy liver is presented, that upon presentation of ‘risk factors’ such as obesity, fructose consumption and/or exposure to endocrine-disrupting chemicals, leads to lipid accumulation (depicted as small yellow dots) in the liver (steatosis), which is the first (reversible) stage of nonalcoholic fatty liver disease (NAFLD). Activation and/or recruitment of macrophages to the liver leads to nonalcoholic steatohepatitis (NASH) and eventual fibrosis. Importantly, progression to NASH and the development of fibrotic and/or cirrhotic lesions (not pictured) represent an irreversible stage of liver disease. Left untreated, a subset of cases culminates in the development of neoplastic events that give rise to hepatocellular carcinoma (HCC), with or without cirrhosis, as the final endpoint of hepatic disease progression.

Figure 2. Altered hepatic metabolic pathways leading to NAFLD

The liver is central to the maintenance of whole-body lipid homeostasis. Mechanistically, uptake of dietary fats is facilitated by release of bile acids that are synthesized in the liver and secreted by the gall bladder into the intestine. Bile salts emulsify fat, creating free fatty acids (FFAs) and monoglycerides, which are rapidly absorbed by enterocytes of the intestine. In the intestine, FFAs and monoglycerides are resynthesized into triglycerides, which are packaged into chylomicrons and are taken up by the liver via receptor-mediated endocytosis. The liver is also is responsible for converting carbohydrates and protein into FFAs, which are packaged into triglycerides and exported from the liver as VLDL. The liver is also the primary source of β-oxidation that serves to metabolize FFAs to produce energy in the form of ATP, as well as to generate ketone bodies that are used as an alternative fuel source during periods of fasting. Altogether the balance between lipid uptake and release, triglyceride synthesis and β-oxidation helps to preserve energy homeostasis in the liver. Disruption of these processes by a high-fat diet (HFD) is accompanied by aberrant lipid accumulation in the liver, which leads to a cascade of pathologies ranging from steatosis to hepatocellular carcinoma. Endocrine-disrupting chemicals (EDCs) can also promote nonalcoholic fatty liver disease (NAFLD), either alone or with a HFD, by increasing FFA uptake, increasing de novo lipogenesis, decreasing triglyceride export via VLDL, and/or decreasing FFA β-oxidation.

Figure 3. NR-mediated effects of EDCs on fatty liver development

a The NR1 subfamily of nuclear hormone receptors (NRs) heterodimerize with retinoid X receptors (RXRs) to either promote (pregnane X receptor (PXR) or liver X receptor (LXR)) or inhibit (peroxisome proliferator-activated receptors (PPARs), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), and thyroid receptors (TRs)) hepatic steatosis upon binding their naturally occurring agonist ligands. Select endocrine-disrupting chemicals (EDCs) known to bind these NRs and affect their activity are depicted at the bottom of the figure. For example, tributyltin (TBT) binding RXR–PPAR enhances steatosis, unlike natural free fatty acid ligands. LXR activates lipogenic genes upon binding its natural ligands (oxysterols) and promotes steatosis, but whether its activity is modulated by specific EDCs is currently unclear. b Another major class of NRs that bind EDCs is the steroid receptors such as the androgen receptor (AR), glucocorticoid receptor (GR) and oestrogen receptor (ER). Steroid hormones can either increase (glucocorticoid) or decrease (oestrogen and androgen) hepatic steatosis. Select EDCs known to bind these NRs and affect their activity are depicted at the bottom of the figure. c Aryl hydrocarbon receptor (AhR) represents the third major NR effector of EDC action in the liver. AhR binds EDCs, such as dioxins and polychlorinated biphenyls (PCBs), leading to enhanced steatosis. BPA, bisphenol A; DDE, dichlorodiphenyldichloroethylene; DDT, dichlorodiphenyltrichloroethane; DEHP, di-2-ethylhexyl phthalate; PFOA, perfluorooctanoic acid; PFOS, perfluorooctane sulfonate.

Figure 4. Potential genomic mechanism of EDC action

Once an endocrine-disrupting chemical (EDC) enters the liver, it is bound by specific nuclear hormone receptors (NRs). This action can either positively or negatively affect transcription of lipid homeostasis genes via specific EDC–NR complexes that recruit coactivators or corepressors to target genes. Key coactivators that modulate fatty liver progression include steroid receptor coactivators (SRCs), peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and mediator of RNA polymerase II transcription subunit 1 (MED1), whereas nuclear receptor corepressor (NCoR)–silencing mediator of retinoic acid and thyroid hormone receptor (SMRT)–histone deacetylase 3 (HDAC3) complexes, receptor-interacting protein 140 (RIP140) and ligand-dependent corepressor (LCOR) act as corepressors. Coactivator complexes induce histone modifications associated with active gene transcription, such as acetylation (Ac) and methylation (Me), whereas corepressors generally utilize associated histone deacetylases or demethylases to remove these marks. SRCs and NCoR are subject to regulatory phosphorylation (P) events. Engagement of coregulators by EDC-bound NRs results in modulation of lipid homeostasis gene cassettes and/or reprogramming of the epigenome, which ultimately promotes NAFLD: for example, via enhanced lipogenesis gene expression and/or inhibition of free fatty acid-oxidation gene expression.

Figure 5. Epigenomic action of ‘writers’ of DNA or histone methylation

Specific arginine and lysine residues on histone tails are methylated by distinct histone methyltransferases (HMTs), whereas DNA methylation occurs via the action of DNA methyltransferases (DNMTs). Both HMTs and DNMTs utilize S-Adenosyl methionine (SAM) as their methyl (Me) donor. SAM is created from methionine and its levels are influenced by methionine and interconnected folate cycles. Importantly, high folate maternal diets have been shown to affect DNA methylation patterns in rodent offspring^–. F-THF, 10-formyltetrahydrofolate; me-THF, 5,10-methylene-THF; MTHF, 5-methyltetrahydrofolate; SAH, S-Adenosyl-L-homocysteine; THF, tetrahydrofolate.

Figure 6. Early-life exposure to EDCs trigger the development of NAFLD

Exposure to endocrine-disrupting chemicals (EDCs) during the prenatal period (a critical ‘window of susceptibility’) can result in changes to the liver epigenome that influence susceptibility to liver disease in adulthood. The activity of epigenetic ‘writers’ of DNA (DNA methyltransferases; DNMTs) or histone (histone methyltransferases; HMTs) methyl marks (Me) or ‘erasers’ of these heritable marks (ten-eleven translocation (TET) or histone demethylases (HDMs), respectively) can be influenced by a prenatal EDC exposure, which changes their activity and alters the epigenome. Such epigenetic reprogramming could confer a propensity to develop nonalcoholic fatty liver disease (NAFLD) in adulthood via reprogrammed expression of genes involved in lipid homeostasis.

Figure 7. EDCs and NAFLD risk across the life-course

Endocrine-disrupting chemicals (EDCs) can alter susceptibility to develop nonalcoholic fatty liver disease (NAFLD) via early-life effects that increase susceptibility to obesity and alter hepatic ‘set-points that favour the development of fatty liver, and later-life effects that contribute to the development of liver disease alone or in combination with other NAFLD risk factors such as diet, diabetes mellitus and/or obesity. HFD, high-fat diet; NASH, nonalcoholic steatohepatitis.