Polychlorinated Biphenyls and Nonalcoholic Fatty Liver Disease

Abstract

Polychlorinated biphenyls (PCBs) have been associated with abnormal liver enzymes and suspected nonalcoholic fatty liver disease (NAFLD) in cohort studies. NAFLD affects greater than 25% of the global population and may result in liver-related mortality. Both dioxin-like and non-dioxin-like PCBs have been associated with NAFLD, but their effects and mechanisms differ. Dioxin-like PCBs altered the gut:liver axis and microbiome and caused hepatic steatosis by disrupting hepatic lipid metabolism. In contrast, NDL PCBs reduced the liver’s protective responses to promote diet-induced NAFLD. Mechanisms included the disruption of phosphoprotein signaling resulting in altered nuclear receptor function.

Graphical Abstract

INTRODUCTION:

Polychlorinated biphenyls (PCBs) have been associated with liver injury since 1937, when three cases of fatal jaundice were reported in workers exposed to PCBs and chlorinated naphthalenes [1]. In 1981, dose-dependent liver enzyme elevation and hepatomegaly was reported in PCB-exposed electrical workers [2]. In the United States, PCBs were manufactured by Monsanto under trade names including Aroclor® for industrial applications including dielectric and hydraulic fluids. Monsanto’s material safety data sheet (MSDS #M00018515) reported that “The consistent finding in animal studies is that PCBs produce liver injury following prolonged and repeated exposure by any route, if the exposure is of sufficient degree and duration. Liver injury is produced first, and by exposures that are less than those reported to cause cancer in rodents. Therefore, exposure by all routes should be kept sufficiently low to prevent liver injury.” Despite their historical role in occupational hepatotoxicity, PCBs were only recently associated with an environmental liver disease consistent with nonalcoholic fatty liver disease (NAFLD) [3, 4]. Indeed, PCBs were among the most potent chemicals associated with hepatic steatosis in archived rodent toxicologic pathology studies [5].

Structurally, PCBs are a thermodynamically stable chlorine-substituted biphenyl ring. Approximately 130 of 209 theoretical PCB congeners were commercially produced before PCBs were banned. PCBs are persistent organic pollutants which continue to contaminate the environment, the food supply, breast milk, and even the air in homes and schools. PCBs ranked #5 on the Agency for Toxic Substances and Disease Registry’s 2017 Substance Priority List. All analyzed adult participants in the National Health and Nutrition Examination Survey (NHANES) 2003–2004 had detectable PCB levels in blood [6]. PCB congeners have been classified as either dioxin-like (DL) or non-dioxin-like (NDL) based on their ability to activate the aryl hydrocarbon receptor (AhR) [7]. Both PCB types were associated with suspected NAFLD in a cohort study [3]. PCBs concentrate in adipose and liver. The more highly chlorinated congeners are more resistant to environmental degradation and hepatic metabolism resulting in their bioaccumulation. PCBs undergo enterohepatic circulation, so it is not surprising that they may effect bile acids, the microbiome, and fecal metabolites [8–12].

Global NAFLD prevalence exceeds 25%, and NAFLD may result in liver-related morality or transplantation [13]. NAFLD represents a pathologic spectrum ranging from steatosis to steatohepatitis (NASH) with or without fibrosis, cirrhosis, and hepatocellular carcinoma [14]. A two ‘hit’ hypothesis has been proposed to explain why only some subjects with NAFLD develop progressive liver disease. Classically described second ‘hits’ include insulin resistance, oxidative stress, pro-inflammatory cytokines, organelle dysfunction, as well as alterations in organokines and the intestinal microbiome. NAFLD is often considered the hepatic manifestation of metabolic syndrome. Thus, it is hardly surprising that PCBs, which are endocrine, metabolism and signaling disrupting chemicals (EDCs/MDCs/SDCs) have been associated with NAFLD [15–17]. Recently PCBs were shown to alter organokines previously implicated in NAFLD pathogenesis including fibroblast growth factor-21 (FGF-21), FGF-15, glucagon peptide 1 (GLP-1), leptin and adiponectin [4, 8, 10, 17–22]. MDCs are defined as chemicals that promote obesity, diabetes, fatty liver and/or alterations in lipid and glucose metabolism, but may require a second ‘hit’ such as increased dietary sugar or fat [15]. NDL PCBs including PCB 153 and the Aroclor 1260 PCB mixture worsened diet-induced NAFLD, but did not cause NAFLD in mice fed a normal diet [5, 17, 18, 23–27]. In contrast, DL PCB 126 not only caused NAFLD in rodents fed normal diet, it also worsened diet-induced NAFLD [5, 8, 9, 11, 18–20, 28–30]. SDCs alter intracellular signaling regulating normal hepatic metabolism, cell survival, inflammation, and fibrosis. PCBs inhibited epidermal growth factor receptor (EGFR) signal transduction to alter downstream protein kinase and transcription factor phosphorylation and function in NAFLD models [16, 17, 21–23].

The terms, toxicant associated fatty liver disease and steatohepatitis (TAFLD/TASH), were coined to describe the fatty liver disease associated with industrial chemical exposures [14]. Here TAFLD will be used interchangeably with NAFLD. The U.S. Environmental Protection Agency (EPA)’s hepatic steatosis adverse outcomes pathway (AOP) proposed disruption of cross-talking xenobiotic receptors to be the molecular initiating event for environmental chemicals in TAFLD [31]. Indeed, nuclear receptor dysregulation is a hallmark of NAFLD, and several nuclear receptor agonists are currently in phase III therapeutic clinical trials for this liver disease [32]. Not surprisingly, PCBs altered normal hepatic nuclear receptor signaling [11, 17–20, 22–25, 28, 29, 33, 34] and AhR function [7, 18–20, 22, 28, 29, 33] in NAFLD models. These and other recently described mechanisms are summarized in the Graphical Abstract and Table 1.

TABLE 1.

PCB MECHANSIMS AND EFFECTS IN NAFLD AND LIVER DISEASE

Category	PCB Mechanisms and Effects		Dioxin-like PCBs	Non-dioxin-like PCBs	PCBs*
Steatosis	↑ Steatosis (alone or in combination with either HFD or MCD diet)		[5, 9, 11, 18–20, 28–30]	[5, 24, 26, 27, 43]	[22]
Liver Injury and Cell Death	↑ Liver enzymes		[3, 9, 11, 28, 37, 38, 40, 41]	[3, 4, 25, 37–41]	[2]
	↑ Hepatocyte necrosis		[4]	[4, 17, 25]	-
Inflammation	↑ Liver and/or systemic inflammation (e.g., cytokines)		[8, 9, 11, 18, 28, 43]	[4, 18, 24, 25, 27, 34, 43]	[22]
Fibrosis	↑ Fibrosis and/or cytoskeletal remodeling		[11, 18, 28]	[18, 23]	-
AhR and Nuclear Receptors	↑ AhR activation		[18–20, 28, 29, 33]	-	[19, 22]
	Δ Nuclear receptors (e.g., PXR, CAR, PPARα/δ/γ, HNF4α, FXR, ESR1, TRα, LXRα/β, RXR, etc.)		[11, 18–20, 28, 29, 33]	[17–19, 23–25, 33, 34]	[19, 22]
Endocrine Disruption	Pancreatic hormones	Δ Insulin and/or insulin signaling	↑ [8]	↓ [4, 17, 18, 25, 34]	-
	Adipokines	↓ Leptin and/or STAT3 expression	[20]	[4, 17, 21]	[22]
	Enterokines	↑ FGF-15	-	-	[10]
		↓ GLP-1	[8]	-	-
	Hepatokines	Δ FGF-21	↓ [18–20]	↓ [19]	↑ [19]
		Δ Insulin-like growth factor 1(IGF-1)	↑ [19]	↑ [19]	↔ [19]
		Δ Betatrophin	↔ [19]	↑ [19]	↓ [19]
Metabolism Disruption	Δ Hepatic lipid metabolism (e.g., mitochondrial dysfunction) and/or blood lipids		[9, 11, 18–20, 28, 42]	[17–19, 23–25, 27, 34]	[19, 22]
	↓ Gluconeogenesis		[18–20, 28, 29, 42]	[18, 25, 26]	-
Phosphoprotein Signaling Disruption	↓ activation of the EGFR, other kinases, and their targets (e.g., AMPK, AKT, mTOR, ERK, PKA, CREB-1, etc.)		[16, 20]	[16, 17, 21, 23]	[19, 22]
Gut: Liver Axis and Microbiome	Diet interaction		[18, 28, 42, 43]	[17, 18, 23–27, 43]	-
	Δ Microbiome or bacterial metabolites		[8, 9, 11, 12, 43]	[43]	[10]
	Δ Bile acids		[11]	-	[10]
	↑ trimethylamine N-oxide (TMAO)		[28]	-	-
Oxidative Stress	↑ oxidative stress or ↓ antioxidant protection (e.g., ↓ NRF2)		[42]	[23, 26, 27]	-
Gene:Environment Interactions	Δ PNPLA3 expression		↓ [19]	↑ [19]	↓ [19, 22]
Sexually Dimorphic Effects	Sex differences		[4, 35]	-	[22]
Clinical Outcomes	↑ Liver-related deaths		-	-	[1, 35]
	↑ Hepatocellular carcinomas		-	-	[35, 36]

^*PCBs in cohort studies where levels of specific PCB congeners were not reported or in animal studies investigating mixtures of DL and NDL PCBs.

COHORT STUDIES INVESTIGATING PCBS IN LIVER DISEASE:

Cohort studies support the rationale to investigate the mechanisms of PCBs in NAFLD. Chronic liver disease mortality was increased in males and liver cancer in females following the Yucheng and Yusho PCB poisoning events [35]. Likewise, liver cancer mortality was increased in some, but not all, studies of PCB-exposed electrical workers [36]. In 2010, multiple PCB congeners were dose-dependently associated with increased odds ratios for ‘unexplained alanine aminotransferase (ALT) elevation’, a surrogate NAFLD biomarker in adult NHANES 2003–2004 [3]. Subsequent NHANES and other cohort studies confirmed the positive association between PCBs and liver enzymes [37–41]. In 2018, a novel combination of serologic liver disease biomarkers investigated TASH in the Anniston Community Health Survey (ACHS) [4]. ACHS is a residential cohort from Anniston, AL, the historical location of a PCB manufacturing complex. In addition to elevated PCB exposures, ACHS participants had a high prevalence of obesity and diabetes placing them at increased risk for steatohepatitis. While diet-induced NASH is characterized by apoptotic hepatocyte death, TASH has frequently been associated with hepatocellular necrosis [14]. Indeed, Aroclor 1260 exposures caused secondary liver necrosis in model systems due to negative caspase-3 regulation by PCB-induced alterations in casein kinase 2 (CK2) structure and function [17]. In order to evaluate hepatocyte apoptosis and necrosis, the cytokeratin 18 (CK18) M30 and M65 serologic biomarkers were measured in ACHS [4]. CK18 is a cytoskeletal protein abundantly expressed in hepatocytes which spills into the blood as either a whole (M65) or caspase-3-cleaved fragment (M30) during cell death. Circulating M30 and M65 are both increased by apoptosis, but only M65 is increased by necrosis. Applying this biomarker combination, a high prevalence of necrotic liver disease (49%) was determined in ACHS. Fifteen of the thirty-five measured PCB congeners were positively associated with necrotic liver disease and/or M65. Next, steatohepatitis second ‘hit’ mechanisms including insulin resistance and serum pro-inflammatory cytokines were assessed [4]. Subjects with necrotic liver disease had significantly increased HOMA-IR, IL-1β, IL-6, and plasminogen activator inhibitor-1 (PAI-1). Thus, ACHS participants had a high prevalence of liver necrosis positively associated with PCB exposures, insulin resistance, and pro-inflammatory cytokines consistent with TASH. ΣPCBs was inversely associated with serum insulin and leptin levels consistent with endocrine disruption. Interestingly, IL-6 and PAI-1 were also increased, while insulin was decreased in an animal model of steatohepatitis due to Aroclor 1260 and high fat diet (HFD) co-exposures [25]. While leptin was not decreased in this model, PCBs greatly reduced signal transducer and activator of transcription 3 (STAT3) expression and leptin signaling [17, 21]. Unfortunately, liver biopsy is not available to confirm the suspected steatohepatitis observed in the cohort studies.

MECHANISMS OF DIOXIN-LIKE PCBS IN FATTY LIVER DISEASE:

PCBs 77 and 126 caused steatosis or worsened diet-induced steatosis by increasing hepatic triglycerides, free fatty acids, and cholesterol in rodent models [9, 11, 18–20, 28–30]. Applying EPA’s NAFLD AOP, the apical key events responsible for DL PCB-induced steatosis were: (i) increased lipid influx (via upregulation CD36 and fatty acid binding protein-1); (ii) decreased lipid efflux (via downregulation of apolipoprotein B-100 (ApoB-100)); (iii) decreased fatty acid oxidation (via downregulation of peroxisome proliferator-activated receptor α (PPARα)); despite (iv) inconsistently decreased lipogenesis (via downregulation of fatty acid synthase). The downregulation of ApoB-100 was profound in mice fed methionine-choline deficient (MCD) diet [28], and may have been responsible for the reduced serum lipid levels observed in some studies [11, 19, 28]. PCB 126 reduced hepatic gluconeogenesis (via phosphoenolpyruvate carboxykinase downregulation), and this was associated with fasting hypoglycemia in some studies [18–20, 28, 29, 42]. Liver cell death [3, 4, 9, 11, 28, 37, 38, 40, 41]; inflammation [8, 9, 11, 18, 28, 43]; and fibrosis [11, 18, 28] were increased by DL PCBs.

Recently described mechanisms for DL PCBs in NAFLD include mitochondrial dysfunction and oxidative stress with antioxidant depletion [42]; decreased expression of the protective hepatokine, FGF-21[18–20]; and phosphoprotein signaling disruption [16, 20]. Of all congeners tested, PCB 126 was the most potent inhibitor of EGFR activity [16], and it also reduced downstream protective AMPK and cyclic AMP responsive element binding protein 1 (CREB-1) signaling [20].

Gut bacterial-derived indoles can activate AhR, thereby implicating the AhR in maintenance of intestinal bacteria-host homeostasis [44]. Therefore, it is not surprising that DL PCBs impacted the gut:liver axis and microbiome. Indeed in animal models, DL PCBs altered gut bacteria and their metabolites [8–12, 43], bile acids [10, 11], and enterokines [8, 10]. PCB 126 increased the firmicutes:bacteroidetes ratio; decreased alpha diversity and GLP-1; and altered microbial production of short chain fatty acids [8, 9, 12, 43]. PCB 126-induced gut dysbiosis correlated with fifteen different NAFLD biomarkers involving hepatic steatosis, metabolism and inflammation [9]. PCB 77 increased the firmicutes:bacteroidetes ratio; serum bile acids; and hepatic steatosis, inflammation, and fibrosis [11, 43]. The dose-dependent intestinal dysbiosis induced by a PCB mixture quantitatively and qualitatively altered bile acids as well as ileal Fgf-15 and hepatic Cyp7a1 expression [10].

In contrast to the experimental data, DL PCBs were inversely correlated with the degree of hepatic steatosis and inflammation at baseline in bariatric surgery cohorts [40, 41]. However, PCB levels positively correlated with liver enzymes at 12 months post-operatively suggesting impaired NAFLD resolution with weight loss [41]. While confirmatory data are required, the reported species differences could be due to differential exposures and potencies for AhR activation [45]. Figure 1 summarizes the mechanisms of DL PCBs in NAFLD which included both AhR-dependent and AhR-independent pathways.

Figure 1. Schematic diagram depicting mechanisms of Dioxin-Like PCBs in NAFLD.

Dioxin-Like (DL) PCBs induce pro-inflammatory cytokines, and directly activate the AhR while inhibiting EGFR; leading to signaling disruption and transcriptional reprograming that facilitate hepatic lipid accumulation, inflammation and cell death. DL PCBs, with or without a high caloric diet, alter intestinal microbiota leading to gut dysbiosis thereby promoting host inflammation, disruption of bile acid and short chain fatty acid metabolism, and enterokine production. This, in turn, affects liver function and behavior, further exacerbating NAFLD symptoms.

MECHANISMS OF NON-DIOXIN-LIKE PCBS IN NAFLD:

Rather than causing NAFLD, NDL PCBs attenuate the liver’s protective responses against the deleterious effects of diet-induced obesity to exacerbate diet-induced NAFLD [17, 18, 23–27, 43]. PCB 153, the single most abundant PCB congener in humans, was a diet-dependent obesogen which increased hepatic steatosis (via increased lipid synthesis, influx), oxidative stress, inflammation (via NFKB activation) and the intestinal firmicutes:bacteroidetes ratio [24, 26, 27, 43]. Aroclor 1260 exposures mediated the transition from diet-induced steatosis to steatohepatitis by increasing hepatic necrosis [17, 25], inflammation [18, 25, 34], and fibrosis [18, 23]. Aroclor 1260 altered hepatic lipid metabolism and decreased gluconeogenesis consistent with metabolic disruption [17, 18, 23, 25, 26, 34]. Insulin, leptin, and FGF-21 levels and/or signaling were reduced consistent with endocrine disruption [4, 17–19, 21, 25, 34]. Increased hepatocyte-derived transforming growth factor β (TGF-β) activated pro-fibrotic pathways [23].

Pollutant-induced hepatic nuclear receptor activation and crosstalk were proposed to be molecular initiating events in EPA’s NAFLD AOP [31]. The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are nuclear receptors implicated in hepatic xenobiotic/intermediary metabolism, inflammation, and NAFLD [32]. NDL PCBs ligand-activated human PXR and CAR variants as well as mouse PXR [25, 33]. PCBs indirectly activated mouse and human CAR via high-affinity hydrophobic binding at EGFR’s ligand binding domain to prevent ligand-induced receptor endocytosis and tyrosine kinase activation leading to downstream CAR de-phosphorylation and activation [16, 17, 21, 25, 33]. Perhaps due to similarities with the insulin receptor, the EGFR also regulates numerous pathways involved in liver metabolism, regeneration, and gene expression [46]. By impacting these pathways, PCB-mediated EGFR signaling disruption may explain why Aroclor 1260 worsened HFD-induced NAFLD even in CAR null mice; while the direct CAR agonist, TCPOBOP, was protective [34, 47].

Recently, a proteomics approach determined that Aroclor 1260 negatively regulated the activities of several protective nuclear receptors [23]. These included hepatocyte nuclear factor 4-alpha (HNF4α); farnesoid x receptor (FXR); PPARα/δ/γ; thyroid hormone receptor α (TRα); and others. Agonists for several of these receptors (e.g., FXR, PPARα/δ) are currently in clinical trials for the treatment of NAFLD, suggesting that their negative regulation by PCBs could worsen fatty liver disease. Aroclor 1260 antagonized human PPARα, but not FXR or PPARγ, in vitro suggesting that both direct and indirect mechanisms may have contributed to the observed reductions in nuclear receptor activities [33]. PCBs interacting with diet decreased HNF4α protein and/or mRNA levels [22, 23]. HNF4α is a critical identity gene regulating the expression of the liver’s specific metabolic genes as well as pancreatic insulin production [48]. Therefore, its downregulation may also explain the reduced insulin levels associated with NDL PCB exposures [4, 17, 18, 25, 34]. The activities of other hepatic transcription factors including nuclear factor, erythroid 2 like 2 (NRF2) were also altered [23]. NDL PCB-induced NRF2 down-regulation decreased hepatic glutathione levels, rendering the liver more susceptible to the oxidative stress imposed by the second ‘hit’ of diet induced obesity [23].

The reduction in intracellular phosphoprotein levels associated with PCB exposures has been termed signaling disruption [16, 17]. Because the activity of many transcription factors is regulated by their phosphorylation status, signaling disruption contributed to PCB-induced hepatic transcriptional reprogramming [23]. In an animal model of TASH, hepatic phosphoprotein levels were reduced up to 25% by Aroclor 1260, and these changes negatively impacted multiple steatohepatitis pathways [17]. HFD did not dramatically alter the hepatic signaling capacity of the liver, but exacerbated the negative PCB effect. Decreased kinase function, rather than increased phosphatase activity was responsible for the observed phosphoprotein downregulation. [17]. Many, but not all, affected kinases were downstream of the EGFR. PCB binding sites were identified on the EGFR, and PCBs potently inhibited hepatic EGF-dependent EGFR signaling in vitro/in vivo, and decreased placental EGFR phosphorylation human subjects [16, 17, 21, 49]. NDL PCBs are likely responsible for the majority of PCB-induced EGFR inhibition because they have bio-accumulated to a greater degree in humans. In summary, PCBs antagonized the EGFR to cause signaling disruption (Figure 2) which contributed to the hepatic transcriptional reprogramming which promoted the development of diet-induced steatohepatitis (Figure 3).

FIGURE 2. Schematic diagram highlighting signaling disruption by PCBs in NAFLD.

Non-Dioxin-Like (NDL) PCBs inhibit the EGFR pathway which negatively affects HNF4a and NRF2 activity leading to deficits in metabolism and antioxidant response, respectively. NDL PCBs also diminished hepatic PKA-AMPK-CREB pathway and hepatic FXR and PPARa/d/g activity, further causing metabolic disruption. Both circulating insulin and leptin are diminished with NDL PCBs contributing to diminished activity of the insulin signaling pathway and effector STAT3. In contrast, IL-6 is elevated with NDL PCB exposures contributing to inflammation. NDL PCBs activate xenobiotic receptors, CAR and PXR; these nuclear receptors have agonists in clinical trials currently and could serve as potential targets for TASH to restore metabolic reprogramming of the liver.

FIGURE 3. Schematic diagram depicting mechanisms of Non-Dioxin-Like PCBs in NAFLD.

Non-Dioxin-Like (NDL) PCBs induce pro-inflammatory cytokines, activate CAR and PXR and inhibit EGFR; leading to signaling disruption and transcriptional reprograming that facilitate diet-induced steatohepatitis and fibrosis. NDL PCBs also target extra-hepatic organs including the intestine (in conjunction with a high fat diet), pancreas and adipose tissue, thereby altering the gut microbiome, insulin levels and leptin levels respectively; further exacerbating NAFLD symptoms.

FUTURE DIRECTIONS:

Emerging data implicate PCBs in liver fibrosis [11, 18, 23, 28] and in the gene:environment interactions influencing NAFLD pathogenesis (e.g., patatin-like phospholipase domain-containing protein (PNPLA3) [19, 22]). The hepatic effects of relevant PCB mixtures (e.g., DL plus NDL congeners) differed from the individual components [19]; and sexually dimorphic responses were reported [4, 22, 35]. The potential role of PCBs in the developmental origins of NAFLD remains unknown. These areas warrant future investigation.

CONCLUSIONS:

While PCBs have long been associated with hepatotoxicity, they have only recently been associated with NAFLD. The responsible mechanisms included alterations in: (i) hepatic lipid metabolism, inflammation, and fibrosis; (ii) the gut:liver axis and microbiome; (iii) phosphoprotein signaling disruption resulting in transcriptional reprogramming with attenuated hepatoprotective responses; (iv) endocrine disruption including organokines; and (v) mitochondrial dysfunction with oxidative stress and antioxidant depletion. Interactions between diet and PCBs determined NAFLD severity. Thus, while PCB levels have decreased in the environment, PCBs may only now be impacting NAFLD due to the recent obesity epidemic. More PCB data are needed, particularly from human subjects with biopsy-proven NAFLD.

HIGHLIGHTS:

• Polychlorinated biphenyls (PCBs) are persistent organic pollutants implicated in nonalcoholic fatty liver disease.

• Dioxin-like PCBs altered the gut:liver axis and microbiome and caused hepatic steatosis by disrupting hepatic lipid metabolism.

• Non-dioxin-like PCBs altered hepatic transcriptional programming to promote diet-induced steatohepatitis.

• Broad mechanisms include endocrined, metabolism, and signaling disruption.

ABBREVIATIONS:

ACHS

Anniston Community Health Survey

AhR

aryl hyodrocarbon receptor

AKT

protein kinase B

ALT

alanine aminotransferase

AMPK

AMP-activated protein kinase

AOP

adverse outcome pathway

ApoB-100

apolipoprotein B-100

CAR

constitutive androstane receptor

CK2

casein kinase 2

CK18

cytokeratin 18

CREB-1

cyclic AMP responsive element binding protein 1

Cyp7a1

cytochrome P450 family 7 subfamily A member 1

DL

dioxin-like

EDCs

endocrine disrupting chemicals

EGF

epidermal grow factor

EGFR

epidermal growth factor receptor

EPA

Environmental Protection Agency

ERK

extracellular-regulated protein kinase

ESR1

estrogen receptor 1 or α

FXR

farnesoid x receptor

FGF-15

fibroblast growth factor-15

FGF-21

fibroblast growth factor-21

GLP-1

glucagon-like peptide-1

GCG

glucagon

GCGR

glucagon receptor

GSH

glutathione

HFD

high fat diet

HNF4α

hepatocyte nuclear factor 4-alpha

INSR

insulin receptor

IL6

interleukin 6

IL6R

interleukin 6 receptor

IR

insulin resistance

LXRα/β

liver X receptor α/β

MCD

methionine-choline deficient

MDCs

metabolism disrupting chemicals

mTOR

mammalian target of rapamycin

MSDS

material safety data sheet

LEPR

leptin receptor

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

NDL

non-dioxin-like

NHANES

National Health and Examination Survey

NRF2

nuclear factor erythroid 2-related factor

PAI-1

plasminogen activator inhibitor-1

PCBs

polychlorinated biphenyls

PEPCK

phosphoenolpyruvate carboxykinase

PKA

protein kinase A

PNPLA3

patatin-like phospholipase domain-containing protein 3

PPARα/δ/γ

peroxisome proliferator-activated receptor α/δ/γ

PXR

pregnane X receptor

RXR

retinoid X receptor

SDCs

signaling disrupting chemicals

STAT3

signal transducer and activator of transcription 3

TAFLD

toxicant associated fatty liver disease

TASH

toxicant associated steatohepatitis

TCPOBOP

1,4-Bis-[2-(3,5-dichloropyridyloxy)]benzene, 3,3′,5,5′-Tetrachloro-1,4-bis(pyridyloxy)benzene

TGF-β

transforming growth factor β

TRα

thyroid hormone receptor α