Environmental pollution: a tangible risk for NAFLD pathogenesis

Abstract

The liver is crucial for human life, and the health of this organ often mirrors the health of the individual. The liver can be the target of several diseases, the most prevalent of which, as a consequence of development and changes in human lifestyles, is the nonalcoholic fatty liver disease (NAFLD). NAFLD is a multifactorial disease that embraces many histo-pathologic conditions and is highly linked to metabolic derangements. Technological progress and industrialization have also had the consequence of releasing pollutants in the environment, for instance pesticides or solvents, as well as by-products of discharge, such as the particulate matter. In the last decade, a growing body of evidence has emerged, shedding light on the potential impact of environmental pollutants on liver health and, in particular, on NAFLD occurrence. These contaminants have a great steatogenic potential and need to be considered as tangible NAFLD risk factors. There is an urgent need for a deeper comprehension of their molecular mechanisms of action, as well as for new lines of intervention to reduce their worldwide diffusion. This review wishes to sensitize the community to the effects of several environmental pollutants on liver health.

Figure 1

Inhaled particulate matter promotes hepatic steatosis through inflammation and several molecular and metabolic derangements. Once inhaled, PM reach the lungs alveoli where they cause inflammation. Exposure to PM is associated to systemic inflammation, rise in plasma tryglicerides, LDL and VLDL, pro-inflammatory cytokines and IR. In a secondary phase, particles arrive to the liver where they activate Kupffer cells and promote inflammation through the activation of several molecular pathways (i.e., JNKs-AP1, NF-κB and TLR4). Particles also affect PPARs activity, altering lipid and glucose metabolism. The actions of PM on liver could also be mediated by the metals contained within particles, whose altered content may induce oxidative stress, affecting liver health. PM: particulate matter; LDL: low-density lipoproteins; VLDL: very low-density lipoproteins; IR: insulin resistance; JNKs: c-Jun N-terminal kinases; AP1: activator protein 1; NF-κB: nuclear factor-κB; TLR4: Toll-like receptor 4; PPARs: peroxisome proliferator-activated receptors.

Figure 2

Several water, soil and food contaminants may alter metabolism through different mechanisms of action. Widely used pesticides and herbicides promote the occurrence of hepatic steatosis. To date, one potential mechanism underlying this pathological process involves the activation of the nuclear receptor PXR, which is known to promote the hepatic increase in AMP/ATP ratio and lipid content, as well as to upregulate intestinal lipids uptake (dashed lines indicate the hypothetical mechanism induced by pesticides). Pesticides and herbicides may also induce steatosis, obesity and IR by causing mitochondrial failure. Various studies reported the association of a high exposure to heavy metals (e.g., arsenic, lead, mercury and cadmium) to the incidence of NAFLD, obesity and diabetes, even though the exact mechanisms involved have not yet been elucidated. One of the most important classes of contaminants involved in a wide range of metabolic diseases is represented by the chemical compounds called EDCs. These molecules promote OS and related damage, such as lipid peroxidation, and reduce antioxidant defenses. Another consequence of the EDCs exposure is the onset of a pro-inflammatory state that modulates the expression of specific cytokines and adipokines. In fact, IL6 and TNFα were found to be higher in exposed subjects, whereas adiponectin was reduced. Strictly associated to EDCs, is the downregulation of ISRs and the occurrence of IR. At cellular and molecular levels, however, these molecules are known to induce hepatocellular apoptosis and to bind nuclear receptors (e.g., RXRs and PPARs), thus affecting their activities. This broad range of actions implies their involvement in the onset of several metabolic disorders, such as: diabetes, steatosis, obesity, MetS, PCOS and CVD. PXR: pregnane X receptor; IR: insulin resistance; ALT: alanine transaminase; EDCs: endocrine disruptor compounds; OS: oxidative stress; IL6: interleuchin 6; TNFα: tumor necrosis factor α; ISRs: insulin receptors; RXRs: retinoid X receptors; PPARs: peroxisome proliferator-activated receptors; MeS: metabolic syndrome; PCOS: polycystic ovary syndrome; CVD: cardiovascular disease.