No abstract

Inflammasome activation has been recently recognized to play a central role in the development of drug-induced and obesity-associated liver disease. However, the sources and mechanisms of inflammasome mediated liver damage remain poorly understood. Our aim was to investigate the effect of NLRP3 inflammasome activation on the liver using novel mouse models. We generated global and myeloid cell specific conditional mutant Nlrp3 knock-in mice expressing the D301N Nlrp3 mutation (ortholog of D303N in human NLRP3) resulting in a constitutively activated NLRP3. To study the presence and significance of NLRP3 initiated pyroptotic cell death, we separated hepatocytes from non-parenchymal cells and developed a novel flow cytometry-based (FACS) strategy to detect and quantify pyroptosis in vivo based on detection of active caspase1 and propidium iodide (PI) positive cells. Liver inflammation was quantified histologically, by FACS and via gene expression analysis. Liver fibrosis was assessed by Sirius-Red-staining and qPCR for markers of hepatic stellate cell-(HSC)-activation. NLRP3 activation resulted in shortened survival, poor growth, and severe liver inflammation; characterized by neutrophilic infiltration and HSC-activation with collagen deposition in the liver. These changes were partially attenuated by treatment with anakinra, an interleukin-1 receptor antagonist. Notably, hepatocytes from global Nlrp3 mutant mice showed marked hepatocyte pyroptotic cell death with more than a fivefold increase in active caspase1-PI double positive cells. Myeloid cell restricted mutant NLRP3 activation resulted in a less severe liver phenotype in the absence of detectable pyroptotic hepatocyte cell death. Conclusions Our data demonstrates that global and to a lesser extent myeloid-specific NLRP3 inflammasome activation results in severe liver inflammation and fibrosis, while identifying hepatocyte pyroptotic cell death as a novel mechanism of NLRP3 mediated liver damage.

It is widely known that the liver is a central organ in lipogenesis, gluconeogenesis and cholesterol metabolism. However, over the last decades, a variety of pathological conditions highlighted the importance of metabolic functions within the diseased liver. As observed in Western societies, an increase in the prevalence of obesity and the metabolic syndrome promotes pathophysiological changes that cause non-alcoholic fatty liver disease (NAFLD). NAFLD increases the susceptibility of the liver to acute liver injury and may lead to cirrhosis and hepatocellular cancer. Alterations in insulin response, β-oxidation, lipid storage and transport, autophagy and an imbalance in chemokines and nuclear receptor signaling are held accountable for these changes. Furthermore, recent studies revealed a role for lipid accumulation in inflammation and ER stress in the clinical context of liver regeneration and hepatic carcinogenesis. This review focuses on novel findings related to nuclear receptor signaling - including the vitamin D receptor and the liver receptor homolog 1 - in hepatic lipid and glucose uptake, storage and metabolism in the clinical context of NAFLD, liver regeneration, and cancer.

NAFLD has evolved as a serious public health problem in the USA and around the world. In fact, NASH-the most serious form of NAFLD-is predicted to become the leading cause of liver transplantation in the USA by the year 2020. The pathogenesis of NAFLD and NASH, in particular the mechanisms responsible for liver injury and fibrosis, is the result of a complex interplay between host and environmental factors, and is at the centre of intense investigation. In this Review, we focus on recently uncovered aspects of the genetic, biochemical, immunological and molecular events that are responsible for the development and progression of this highly prevalent and potentially serious disease. These studies bring new insight into this complex disorder and have led to the development of novel therapeutic and diagnostic strategies that might enable a personalized approach in the management of this disease.

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease, and is strongly associated with the metabolic syndrome. In the last decade, it has become apparent that the clinical burden of NAFLD is not restricted to liver-related morbidity or mortality, and the majority of deaths in NAFLD patients are related to cardiovascular disease (CVD) and cancer. These findings have fuelled concerns that NAFLD may be a new, and added risk factor for extrahepatic diseases such as CVD, chronic kidney disease (CKD), colorectal cancer, endocrinopathies (including type 2 diabetes mellitus [T2DM] and thyroid dysfunction), and osteoporosis. In this review we critically appraise key studies on NAFLD-associated extrahepatic disease. There was marked heterogeneity between studies in study design (cross-sectional versus prospective; sample size; presence/absence of well-defined controls), population (ethnic diversity; community-based versus hospitalbased cohorts), and method of NAFLD diagnosis (liver enzymes versus imaging versus biopsy). Taking this into account, the cumulative evidence to date suggests that individuals with NAFLD (specifically, nonalcoholic steatohepatitis) harbor an increased and independent risk of developing CVD, T2DM, CKD, and colorectal neoplasms. We propose future studies are necessary to better understand these risks, and suggest an example of a screening strategy. (HEPATOLOGY 2014;59:1174-1197