Exposure to ambient particulate matter induces a NASH-like phenotype and impairs hepatic glucose metabolism in an animal model

doi:10.1016/j.jhep.2012.08.009

Journal of Hepatology

Volume 58, Issue 1, January 2013, Pages 148-154

https://doi.org/10.1016/j.jhep.2012.08.009 Get rights and content

Background & Aims

Air pollution is a global challenge to public health. Epidemiological studies have linked exposure to ambient particulate matter with aerodynamic diameters <2.5 μm (PM_2.5) to the development of metabolic diseases. In this study, we investigated the effect of PM_2.5 exposure on liver pathogenesis and the mechanism by which ambient PM_2.5 modulates hepatic pathways and glucose homeostasis.

Methods

Using “Ohio’s Air Pollution Exposure System for the Interrogation of Systemic Effects (OASIS)-1”, we performed whole-body exposure of mice to concentrated ambient PM_2.5 for 3 or 10 weeks. Histological analyses, metabolic studies, as well as gene expression and molecular signal transduction analyses were performed to determine the effects and mechanisms by which PM_2.5 exposure promotes liver pathogenesis.

Results

Mice exposed to PM_2.5 for 10 weeks developed a non-alcoholic steatohepatitis (NASH)-like phenotype, characterized by hepatic steatosis, inflammation, and fibrosis. After PM_2.5 exposure, mice displayed impaired hepatic glycogen storage, glucose intolerance, and insulin resistance. Further investigation revealed that exposure to PM_2.5 led to activation of inflammatory response pathways mediated through c-Jun N-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and Toll-like receptor 4 (TLR4), but suppression of the insulin receptor substrate 1 (IRS1)-mediated signaling. Moreover, PM_2.5 exposure repressed expression of the peroxisome proliferator-activated receptor (PPAR)γ and PPARα in the liver.

Conclusions

Our study suggests that PM_2.5 exposure represents a significant “hit” that triggers a NASH-like phenotype and impairs hepatic glucose metabolism. The information from this work has important implications in our understanding of air pollution-associated metabolic disorders.

Introduction

Recent studies have indicated that exposure to fine ambient particulate matter (aerodynamic diameter <2.5 μm, PM_2.5) is closely associated with the pathogenesis of cardiovascular disease and metabolic syndrome [1], [2], [3], [4]. Studies from our group and others suggested that PM_2.5-triggered systemic and pulmonary inflammation (low grade) promotes a variety of maladaptive signaling pathways that may lead to insulin resistance [1], [5], [6]. Consistent with these findings, we have recently demonstrated an important interaction of PM_2.5 exposure with a high-fat diet in promoting metabolic syndrome [1], [6]. These prior studies were focused on lung or adipose pathways in mediating inflammatory responses but had not pronounced effects of PM_2.5 exposure on modulating hepatic pathways associated with metabolic disease.

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases ranging from simple non-alcoholic fatty liver (NAFL), to non-alcoholic steatohepatitis (NASH), to irreversible cirrhosis [7]. NAFLD is considered a precursor or hepatic manifestation of cardiovascular disease and metabolic syndrome. The progression of NASH is explained by a “two-hit” working model [8]. According to this model, steatosis represents the “first hit,” which increases the vulnerability of the liver to various “second hits” induced by endotoxin, saturated fatty acids, inflammatory cytokines, oxidative stress, or other liver injuries. The “second hit” in turn leads to hepatic inflammation and fibrosis, the key features of NASH. Recent works have shown that PM_2.5 exposure can activate Kupffer cells in murine liver tissue, which suggests that PM_2.5 may represent a risk factor for NAFLD progression [9], [10].

In this study, we used a “real-world” PM_2.5 exposure system to perform whole-body exposure of mice to environmentally relevant PM_2.5. We demonstrate that exposure to PM_2.5 causes a NASH-like phenotype and impairs hepatic glycogen storage in animals. Through both in vivo and in vitro analyses, we reveal the signaling pathways through which PM_2.5 exposure promotes NASH-associated activities and impairment of hepatic glucose metabolism.

Section snippets

Exposure of animals to ambient PM_2.5

Mice were exposed to concentrated ambient PM_2.5 or filtered air (FA) in a mobile trailer “Ohio’s Air Pollution Exposure System for the Interrogation of Systemic Effects (OASIS)-1” in Columbus, OH, where most of the PM_2.5 components are attributed to long-range transport (Supplementary Fig. 1) [1]. The concentrated PM_2.5 was generated using a versatile aerosol concentration enrichment system (VACES) as described previously [1], [11]. Mice were exposed to concentrated PM_2.5 at nominal 10× ambient

Mice after inhalation exposure to PM_2.5 develop a NASH-like phenotype

To elucidate in vivo effects of PM_2.5 exposure, male C57BL/6 mice were exposed to concentrated ambient PM_2.5 or filtered air (FA) for 3 or 10 weeks (5 days/week, 6 h/day) in exposure chambers of “OASIS-1”, which was composed of the Midwestern regional background in Columbus, USA, where most of the PM_2.5 is attributed to long-range transport (Supplementary Fig. 1) [9]. It has been demonstrated that the distribution and size of concentrated PM_2.5 in the OASIS-1 exposure chamber air truly reflect

Discussion

In this study, we demonstrate that environmentally relevant PM_2.5 exposure induces a “NASH-like” phenotype and alters glucose/insulin signaling pathways in the murine liver. This work extends our prior observations on the link between air pollution exposure and abnormalities in glucose homeostasis [1], [6]. An important finding in this study is the reduction of hepatic glycogen storage upon PM_2.5 exposure (Fig. 2C–E). Given the central role of hepatic glycogen storage in whole body glucose

Financial support

Portions of this work were supported by National Institutes of Health (NIH) Grants DK090313 and ES017829 to KZ, American Heart Association Grants 0635423Z and 09GRNT2280479 to KZ, NIH Grants ES016588, ES017412, and ES018900 to QS, and NIH grants R01ES019616, R01ES017290, and R01ES015146 to SR.

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

The underlying research reported in the study was funded by the NIH Institutes of Health.

Acknowledgements

We thank Dr. Scott Friedman for providing LX-2 cells and Dr. Michael Tainsky for providing AP-1 reporter plasmids.

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PM_2.5 exposure induced liver injury, mainly characterized by steatosis and fibrosis. The down-regulation and mis-localization of Par3 were important mechanisms of liver injury induced by PM_2.5.
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Information on the relation of air pollution with non-alcoholic fatty liver disease (NAFLD) is scarce. We thus conducted a large cross-sectional study in Asia to investigate the role of air pollution in NAFLD.
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We found positive relationships between PM_2.5 and the odds of NAFLD and advanced fibrosis, with every standard deviation (SD, 7.5 µg/m³) increases in PM_2.5 exposure being associated with a 10% (95% confidence interval [CI]: 9%–11%) increment in the prevalence of NAFLD and an 8% (95% CI: 7%–9%) increment in the prevalence of advanced fibrosis. Similarly, the prevalence of NAFLD and advanced fibrosis increased by 8% (95% CI: 7%–9%) and 7% (95% CI: 6%–8%) with per SD (18.9 µg/m³) increasement in NO₂ concentration, respectively. Additionally, for every SD (9.9 µg/m³) increasement in O₃ concentration, the prevalence of NAFLD and advanced fibrosis decreased by 12% (95% CI: 11%–13%) and 11% (95% CI: 9%–12%), respectively.
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The inflammatory response induced by fine particulate matter (PM_2.5), a common class of air pollutants, is an important trigger for the development of pulmonary fibrosis. However, the specific mechanisms responsible for this phenomenon are yet to be fully understood. To investigate the mechanisms behind the onset and progression of lung fibrosis owing to PM_2.5 exposure, both rats and human bronchial epithelial cells were subjected to varying concentrations of PM_2.5. The involvement of the PPARG/HMGB1/NLRP3 signaling pathway in developing lung fibrosis caused by PM_2.5 was validated through the utilization of a PPARG agonist (rosiglitazone), a PPARG inhibitor (GW9662), and an HMGB1 inhibitor (glycyrrhizin). These outcomes highlighted the downregulation of PPARG expression and activation of the HMGB1/NLRP3 signaling pathway triggered by PM_2.5, thereby eliciting inflammatory responses and promoting pulmonary fibrosis. Additionally, PM_2.5 exposure-induced DNA hypermethylation of PPARG-encoding gene promoter downregulated PPARG expression. Moreover, the DNA methyltransferase inhibitor 5-azacytidine mitigated the hypermethylation of the PPARG-encoding gene promoter triggered by PM_2.5. In conclusion, the HMGB1/NLRP3 signaling pathway was activated in pulmonary fibrosis triggered by PM_2.5 through the hypermethylation of the PPARG-encoding gene promoter.
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Research ArticleExposure to ambient particulate matter induces a NASH-like phenotype and impairs hepatic glucose metabolism in an animal model

Background & Aims

Methods

Results

Conclusions

Introduction

Section snippets

Exposure of animals to ambient PM2.5

Mice after inhalation exposure to PM2.5 develop a NASH-like phenotype

Discussion

Financial support

Conflict of interest

Acknowledgements

Gastroenterology

J Biol Chem

Trends Cell Biol

Am J Gastroenterol

Prog Lipid Res

Curr Opin Cell Biol

J Biol Chem

Ambient air pollution exaggerates adipose inflammation and insulin resistance in a mouse model of diet-induced obesity

Circulation

Metabolic syndrome and inflammatory responses to long-term particulate air pollutants

Environ Health Perspect

Traffic-related air pollution and incident type 2 diabetes: results from the SALIA cohort study

Environ Health Perspect

Association between fine particulate matter and diabetes prevalence in the US

Diabetes Care

The relationship between diabetes mellitus and traffic-related air pollution

J Occup Environ Med

Effect of early particulate air pollution exposure on obesity in mice: role of p47phox

Arterioscler Thromb Vasc Biol

Non-alcoholic steatohepatitis: definition and pathology

Semin Liver Dis

Airborne particulate matter selectively activates endoplasmic reticulum stress response in the lung and liver tissues

Am J Physiol Cell Physiol

Research Article
Exposure to ambient particulate matter induces a NASH-like phenotype and impairs hepatic glucose metabolism in an animal model

Exposure of animals to ambient PM_2.5

Mice after inhalation exposure to PM_2.5 develop a NASH-like phenotype