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Non-alcoholic fatty liver disease (NAFLD) is a chronic liver condition that affects millions of individuals in the United States, of which approximately twenty percent of cases progress to non-alcoholic steato-hepatitis (NASH). NASH is characterized by macro-vascular steatosis and persistent inflammation in the liver, which can lead to fibrosis. Evidence suggests potential effects of NAFLD and NASH on the devel-opment of pulmonary pathologies, but the interaction between the liver and the lung is not well under-stood. In this study, we assessed the impact of NASH development on lung inflammation and fibrosis over time. Male C57BL/6J mice were fed control (10% kCal) or high-fat (HFD) (60% kCal) diets. Liver tissue, lung tissue, and bronchoalveolar lavage (BAL) fluid were collected after 1, 3, and 6 months of feeding. Histopathologic evaluation of livers from HFD-fed mice at 6 months confirmed the development of NASH. In the lung, we observed histopathologic al-terations, including inflammatory cell infiltration, li-pid-laden macrophages, septal damage, and epi-thelial thickening at 6 months. Gene expression anal-ysis of whole lung tissue revealed changes in genes related to inflammation (IL-1B), fibrosis (CTGF), and lipid metabolism (ApoA1). These results characterize an association of pulmonary complications during simple steatosis to NASH transition, suggesting lung-liver crosstalk.

Recent studies have investigated the roles of FXR deficiency in the pathogenesis of alcoholic liver disease (ALD). However, the underlying molecular mechanisms remain unclear. In this study, FXR knockout (FXR-/-) and wild-type (WT) mice were subjected to chronic-plus-binge alcohol feeding to study the effect of FXR deficiency on ALD development. The degree of liver injury was greater in FXR-/- mice compared to WT mice. Ethanol feeding enhanced hepatic steatosis in FXR-/- mice, accompanied by decreased mRNA levels of Pparα and Srebp-1c. The expression of Lcn2 was increased by ethanol treatment, despite unchanged expression of pro-inflammatory cytokines Tnfα, Il6 and Il-1β. Furthermore, ethanol treatment altered bile acid (BA) homeostasis to a greater extent in FXR-/- mice, as well as serum and hepatic BA pool composition. The mRNA levels of hepatic Cyp7a1 and Shp, as well as intestinal Fgf15, were decreased in WT mice with ethanol feeding, which were further reduced in FXR-/- mice. Levels of both primary and secondary BAs were markedly elevated in FXR-/- mice, which were further increased after ethanol treatment. Moreover, hepatic MAPK signaling pathways were disturbed presumably by increased hepatic BA levels. In summary, FXR deficiency increased hepatic steatosis and altered BA pool composition, contributing to worsened liver toxicity.

Emerging evidence has shown that FXR activation ameliorates the development of alcoholic liver diseases (ALD) while whole-body deficiency of FXR in mice leads to more severe ALD. However, it’s unknown whether the enhanced susceptibility to ALD development in FXR(−/−) mice is due to deficiency of hepatic FXR or increased toxicity secondary to increased bile acid (BA) levels. Hepatocyte-specific FXR knockout mice (FXR(hep−/−)) present similar BA levels compared to wild-type mice, and are therefore a useful model to study a direct role of hepatic FXR in ALD development. FXR(hep−/−) mice were subject to an ALD model with chronic plus binge drinking of alcohol to determine the effects of hepatic FXR deficiency on ALD development. The FXR(hep−/−) mice showed an altered expression of genes involved in BA and lipid homeostasis with alcohol treatment. Despite a slightly increased trend in hepatic lipid deposition and collagen accumulation in FXR(hep−/−) mice, there were no significant differences in the severity of steatosis, inflammation, or fibrosis between WT and FXR(hep−/−) mice. Therefore, these findings indicate that FXR deficiency in hepatocytes might only play a minor role in ALD development. Deficiency of FXR in other non-hepatic tissues and/or increased BA levels resultant from whole-body FXR deficiency might be responsible for more severe ALD development.

PURPOSE OF REVIEW: Environmental contaminants are considered one of major factors in the development and progression of NAFLD, the most common liver disease in the U.S. RECENT FINDINGS: The evolving knowledge of mechanisms of hepatic steatosis and steatohepatitis has recently been reviewed and characterized as ALD, NAFLD, and TAFLD. The most recent mechanistic studies on PFAS and PCBs have revealed a greater role for toxicants in the initiation of not only TAFLD, but also NAFLD and the more progressive inflammatory stage of NAFLD, non-alcoholic steatohepatitis. In addition to insecticides, recent studies support a significant contribution of fungicides and herbicides to NAFLD. SUMMARY: The mechanisms of PFAS, PCBs and fungicides in contributing to the increased prevalence of NAFLD remains unclear. Addressing whether chronic, low-dose exposures could result in liver pathology and whether real-world exposure to mixtures of environmental contaminants pose a significant risk factor for NAFLD is paramount to understand the impact of NAFLD on populations today.

About 15–25% of patients with simple steatosis of nonalcoholic fatty liver disease progresses to nonalcoholic steatohepatitis (NASH), and the underlying mechanism for this progression has not been elucidated. NASH ultimately could progress to cirrhosis, an irreversible condition. Farnesoid X receptor (FXR) has been studied for its role in modulating inflammation, and the expression of FXR is down-regulated during NASH development. FXR deficiency has shown to progress and exacerbate NASH development, and FXR activation has been protective against liver inflammation associated with NASH. The expression of factors in both the adaptive and innate immune response in the liver are regulated in a FXR-dependent and -independent manner. Therefore, understanding key signaling pathways of liver inflammation in NASH is important to determine essential components that predispose, progress, or exacerbate NASH. FXR has been identified as a therapeutic target for NASH to prevent liver inflammation.