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

Abstract

Background Air pollution is a global challenge to public health. Epidemiological studies have linked exposure to ambient particulate matter with aerodynamic diameters < 2.5 μm (PM2.5) to the development of metabolic diseases. In this study, we investigated the effect of PM2.5 exposure on liver pathogenesis and the mechanism by which ambient PM2.5 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 PM2.5 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 PM2.5 exposure promotes liver pathogenesis. Results Mice exposed to PM2.5 for 10 weeks developed a non-alcoholic steatohepatitis (NASH)-like phenotype, characterized by hepatic steatosis, inflammation, and fibrosis. Mice after PM2.5 exposure displayed impaired hepatic glycogen storage, glucose intolerance, and insulin resistance. Further investigation revealed that exposure to PM2.5 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, PM2.5 exposure repressed expression of the peroxisome proliferator-activated receptor (PPAR) γ and PPARα in the liver. Conclusions Our study suggests that PM2.5 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.

Air-Pollution and Cardiometabolic Diseases (AIRCMD): A prospective study investigating the impact of air pollution exposure and propensity for type II diabetes

“…While concern over environmental issues in countries such as China and India have mounted in the last few years, the awareness or knowledge that pervasive environmental toxins may pose a risk for chronic cardiovascular and CM diseases is rather limited. Our previous studies, along with others, have provided credible initial evidence in experimental animal models that inhaled particulates such as air-pollution may indeed interact with other risk factors in predisposing to T2DM via a variety of mechanisms including potentiation of inflammation, promotion of endoplasmic reticulum (ER) stress, alteration in brown adipose tissue function and change in autonomic tone 5, 12, 14–17, 25–29 . However, there is still inadequate prospective information from urban environments exposed to high levels of air-pollution over chronic durations that will allow discernment of potential threshold concentrations for health responses and interaction with other common factors such as diet, activity and exercise.…”

Inhaled ozone (O3)-induces changes in serum metabolomic and liver transcriptomic profiles in rats

“…O 3 exposure also changed the expression of several genes involved in inflammatory processes that tended to be inhibited rather than induced. Air pollution has been recently linked to non-alcoholic liver disease, also known as liver steatohepatitis (Zheng et al, 2013; Lin et al, 2014). One experimental study involving long-term exposure to concentrated ambient PM has shown liver inflammation, fibrosis and changes in markers of insulin signaling (Zheng et al, 2013).…”

“…Air pollution has been recently linked to non-alcoholic liver disease, also known as liver steatohepatitis (Zheng et al, 2013; Lin et al, 2014). One experimental study involving long-term exposure to concentrated ambient PM has shown liver inflammation, fibrosis and changes in markers of insulin signaling (Zheng et al, 2013). Marked acute effects of O 3 on liver gene expression reflecting apoptosis, alteration of mitochondrial function and metabolic processes in the present study support the hypothesis that air pollutants could, over a long period of time, induce liver disease.…”

Ozone Exposure Triggers Insulin Resistance Through Muscle c-Jun N-Terminal Kinase Activation

“…Increased serine phosphorylation of IRS-1 is indeed triggered by many diabetogenic factors, especially through the stress signaling pathways that have been shown to contribute to the development of IR (51). PM 2.5 exposure activates JNK and downregulates the IRS1-mediated signaling in the liver, leading to glucose intolerance and IR (52). In addition, specific overexpression of a constitutively active JNK in skeletal muscle has been shown to be sufficient to induce whole-body IR through impairment of insulin signaling (53).…”