Non-alcoholic fatty liver disease (NAFLD) is a complex disease, affecting not just the liver, but also all other organs in the body. Despite an increasing amount of people worldwide developing NAFLD ...and having it progress to non-alcoholic steatohepatitis (NASH) and potentially cirrhosis, there is still no approved therapy. Therefore, huge efforts are being made to find and develop a successful treatment. One of the special interests is understanding the liver-gut axis and especially the role of bile acids in the progression of NAFLD. Farnesoid X receptor (FXR)-agonists have been approved und used in other liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), and have shown signs of being able to decrease inflammation and potentially steatosis. This review will mainly focus on targets/ligands that play an important role in bile acid metabolism and give an overview of ongoing clinical as well as pre-clinical trials. With the complexity of the issue, we did not aim at giving a complete review, rather highlighting important targets and potential treatments that could be approved for NAFLD/NASH treatment within the next few years.
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 hospital‐based 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)
Inflammasome activation plays 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 hyperactive NLRP3. To study the presence and significance of NLRP3‐initiated pyroptotic cell death, we separated hepatocytes from nonparenchymal cells and developed a novel flow‐cytometry–based (fluorescence‐activated cell sorting; FACS) strategy to detect and quantify pyroptosis in vivo based on detection of active caspase 1 (Casp1)‐ and propidium iodide (PI)‐positive cells. Liver inflammation was quantified histologically by FACS and gene expression analysis. Liver fibrosis was assessed by Sirius Red staining and quantitative polymerase chain reaction 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 5‐fold increase in active Casp1/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 demonstrate 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. (Hepatology 2014;59:898–910)
NLR inflammasomes, caspase 1 activation platforms critical for processing key pro-inflammatory cytokines, have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). As the ...direct role of the NLRP3 inflammasome remains unclear, we tested effects of persistent NLRP3 activation as a contributor to NAFLD development and, in particular, as a modulator of progression from benign hepatic steatosis to steatohepatitis during diet-induced NAFLD. Gain of function tamoxifen-inducible
Nlrp3
knock-in mice allowing for in vivo temporal control of NLRP3 activation and loss of function
Nlrp3
knockout mice were placed on short-term choline-deficient amino acid-defined (CDAA) diet, to induce isolated hepatic steatosis or long-term CDAA exposure, to induce severe steatohepatitis and fibrosis, respectively. Expression of NLRP3 associated proteins was assessed in liver biopsies of a well-characterized group of patients with the full spectrum of NAFLD.
Nlrp3
−/−
mice were protected from long-term feeding CDAA-induced hepatomegaly, liver injury, and infiltration of activated macrophages. More importantly,
Nlrp3
−/−
mice showed marked protection from CDAA-induced liver fibrosis. After 4 weeks on CDAA diet, wild-type (WT) animals showed isolated hepatic steatosis while
Nlrp3
knock-in mice showed severe liver inflammation, with increased infiltration of activated macrophages and early signs of liver fibrosis. In the liver samples of patients with NAFLD, inflammasome components were significantly increased in those patients with nonalcoholic steatohepatitis (NASH) when compared to those with non-NASH NAFLD with mRNA levels of pro-IL1 beta correlated to levels of COL1A1. Our study uncovers a crucial role for the NLRP3 inflammasome in the development of NAFLD. These findings may lead to novel therapeutic strategies aimed at halting the progression of hepatic steatosis to the more severe forms of this disease.
Key message
Mice with NLRP3 inflammasome loss of function are protected from diet-induced steatohepatitis.
NLRP3 inflammasome gain of function leads to early and severe onset of diet-induced steatohepatitis in mice.
Patients with severe NAFLD exhibit increased levels of NLRP3 inflammasome components and levels of pro-IL1β mRNA correlate with the expression of COL1A1.
Summary 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.
The incidence of obesity has dramatically increased in recent years. Consequently, obesity and associated disorders such as nonalcoholic fatty liver disease (NAFLD) constitute a serious threat. ...Therefore, the contribution of visceral adipose tissue to metabolic homeostasis has become a focus of interest. Visceral adipose tissue secretes free fatty acids (FFAs) and hormones, known as adipokines, and thus seems to play a major role in the development of NAFLD. Apoptotic cell death is a prominent feature in nonalcoholic steatohepatitis (NASH). Indeed, toxic FFAs can activate the intrinsic apoptosis pathway in hepatocytes via c-Jun N-terminal kinase (JNK). JNK activates the proapoptotic protein Bim, resulting in Bax activation and enhanced apoptosis, termed 'lipoapoptosis'. Reduced adiponectin levels may establish a proinflammatory milieu, thus increasing vulnerability to lipotoxicity, which promotes progression from simple steatosis to NASH and even advanced hepatic fibrosis. Moreover, obesity seems to be a risk factor for hepatocellular carcinoma, the most frequent liver cancer subtype. Even in acute liver failure, a high body mass index is associated with poor outcome, and recent data suggest a major role of obesity in the progression of chronic hepatitis C and B. This review summarizes current knowledge - highlighting the inflammatory and cytokine view - of the intimate relationship between adipose and liver tissue.
The burden of chronic liver disease is globally increasing at an alarming rate. Chronic liver injury leads to liver inflammation and fibrosis (LF) as critical determinants of long-term outcomes such ...as cirrhosis, liver cancer, and mortality. LF is a wound-healing process characterized by excessive deposition of extracellular matrix (ECM) proteins due to the activation of hepatic stellate cells (HSCs). In the healthy liver, quiescent HSCs metabolize and store retinoids. Upon fibrogenic activation, quiescent HSCs transdifferentiate into myofibroblasts; lose their vitamin A; upregulate α-smooth muscle actin; and produce proinflammatory soluble mediators, collagens, and inhibitors of ECM degradation. Activated HSCs are the main effector cells during hepatic fibrogenesis. In addition, the accumulation and activation of profibrogenic macrophages in response to hepatocyte death play a critical role in the initiation of HSC activation and survival. The main source of myofibroblasts is resident HSCs. Activated HSCs migrate to the site of active fibrogenesis to initiate the formation of a fibrous scar. Single-cell technologies revealed that quiescent HSCs are highly homogenous, while activated HSCs/myofibroblasts are much more heterogeneous. The complex process of inflammation results from the response of various hepatic cells to hepatocellular death and inflammatory signals related to intrahepatic injury pathways or extrahepatic mediators. Inflammatory processes modulate fibrogenesis by activating HSCs and, in turn, drive immune mechanisms via cytokines and chemokines. Increasing evidence also suggests that cellular stress responses contribute to fibrogenesis. Recent data demonstrated that LF can revert even at advanced stages of cirrhosis if the underlying cause is eliminated, which inhibits the inflammatory and profibrogenic cells. However, despite numerous clinical studies on plausible drug candidates, an approved antifibrotic therapy still remains elusive. This state-of-the-art review presents cellular and molecular mechanisms involved in hepatic fibrogenesis and its resolution, as well as comprehensively discusses the drivers linking liver injury to chronic liver inflammation and LF.
Background: Non-alcoholic fatty liver disease (NAFLD) is the leading chronic hepatic condition worldwide and new approaches to management and treatment are limited. Summary: L-ornithine L-aspartate ...(LOLA) has hepatoprotective properties in patients with fatty liver of diverse etiology and results of a multicenter randomized clinical trial reveal that 12 weeks treatment with oral LOLA (6–9 g/d) results in a dose-related reduction in activities of liver enzymes and triglycerides together with significant improvements of liver/spleen CT ratios. A preliminary report described improvements of hepatic microcirculation in patients with non-alcoholic steatohepatitis (NASH) following treatment with LOLA. Mechanisms responsible for the beneficial effects of LOLA in NAFLD/NASH involve, in addition to its established ammonia-lowering effect, metabolic transformations of the LOLA-constituent amino acids L-ornithine and L-aspartate into L-glutamine, L-arginine, and glutathione. These metabolites have well-established actions implicated in the prevention of lipid peroxidation, improvement of hepatic microcirculation in addition to anti-inflammatory, and anti-oxidant properties. Key Messages: (1) LOLA is effective for the treatment of key indices in NAFLD/NASH. (2) Mechanisms other than LOLA’s ammonia-lowering action have been postulated. (3) Further assessments in the clinical setting are now required.
Abrupt temperature shift from hypothermia to normothermia incurred on reperfusion of organ grafts has been delineated as a genuine factor contributing to reperfusion injury and graft dysfunction ...after transplantation.
In a first clinical series of 6 patients, cold-stored livers, all allocated by the rescue offer mechanism by Eurotransplant, were subjected to machine-assisted slow controlled oxygenated rewarming (COR) for 90 minutes before engrafting. A historical cohort of 106 patients basically similar in graft (all rescue offer organs) and recipient factors was used for comparison.
The clinical benefit of COR was documented by a significant reduction by approximately 50% in peak serum transaminases after transplantation compared to untreated controls (AST 563.5 vs. 1204 U/L, P = 0.023). After 6 months graft survival was 100% in the COR group and 80.9% in the controls (P = 0.24). Respective patient survival was 100% and 84.7% (P = 0.28). Real-time assessment of glucose concentration in the perfusion solution correlated well with postoperative synthetic graft function (r = 0.78; P < 0.02). All treated recipients had normal liver function after a 6-month follow-up and are well and alive.
This first clinical application suggests that controlled graft rewarming after cold storage is a feasible and safe method in clinical praxis and might become an adjunct in organ preservation.
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