Hepatocyte apoptosis is tumor promoting in murine nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease is the most common chronic liver disease and may progress to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). The molecular determinants of this pathogenic progression, however, remain largely undefined. Since liver tumorigenesis is driven by apoptosis, we examined the effect of overt hepatocyte apoptosis in a mouse model of NASH using mice lacking myeloid cell leukemia 1 (Mcl1), a pro-survival member of the BCL-2 protein family. Hepatocyte-specific Mcl1 knockout (Mcl1$^{∆hep}$) mice and control littermates were fed chow or FFC (high saturated fat, fructose, and cholesterol) diet, which induces NASH, for 4 and 10 months. Thereafter, liver injury, inflammation, fibrosis, and tumor development were evaluated biochemically and histologically. Mcl1$^{∆hep}$ mice fed with the FFC diet for 4 months displayed a marked increase in liver injury, hepatocyte apoptosis, hepatocyte proliferation, macrophage-associated liver inflammation, and pericellular fibrosis in contrast to chow-fed Mcl1$^{∆hep}$ and FFC diet-fed Mcl1-expressing littermates. After 10 months of feeding, 78% of FFC diet-fed Mcl1$^{∆hep}$ mice developed liver tumors compared to 38% of chow-fed mice of the same genotype. Tumors in FFC diet-fed Mcl1$^{∆hep}$ mice were characterized by cytologic atypia, altered liver architecture, immunopositivity for glutamine synthetase, and histologically qualified as HCC. In conclusion, this study provides evidence that excessive hepatocyte apoptosis exacerbates the NASH phenotype with enhancement of tumorigenesis in mice

Randomised clinical trial: emricasan versus placebo significantly decreases ALT and caspase 3/7 activation in subjects with non‐alcoholic fatty liver disease

Background: Lipotoxicity leading to excessive caspase‐mediated apoptosis and inflammation is believed to drive liver damage in NAFLD. Emricasan is a pan‐caspase inhibitor that decreased serum ALT and apoptotic and inflammatory markers in subjects with chronic hepatitis. Aims: To assess whether 28 days of emricasan would reduce elevated levels of serum ALT, AST, cleaved cytokeratin‐18, full‐length cytokeratin‐18, and caspase 3/7 in subjects with NAFLD and raised aminotransferases. Methods: Double‐blind, placebo‐controlled, office‐practice study assessed the efficacy, safety, and tolerability of emricasan in subjects with NAFLD and ALT levels ≥1.5 x ULN during screening. Subjects were randomised to emricasan 25 mg twice daily or matching placebo. Subjects with cirrhosis and other causes for raised aminotransferases were excluded. The primary endpoint was the change in ALT at day 28 in the emricasan group vs placebo. Results: 38 subjects were randomised, 19 each to emricasan or placebo. Baseline disease factors were well balanced except for lower median ALT values in emricasan subjects. Three subjects randomised to placebo discontinued prior to day 28. ALT values decreased significantly in emricasan‐treated subjects vs placebo at days 7 (P < 0.0001) and 28 (P = 0.02). cCK18 (day 7), flCK18 (days 7 and 28), and caspase 3/7 (day 7) were also significantly decreased in emricasan‐treated subjects vs placebo. Emricasan treatment was generally safe and well tolerated. Conclusions: Emricasan decreased ALT and biomarkers in subjects with NAFLD and raised aminotransferases after 28 days. These results support the further development of emricasan in patients with NAFLD

Extracellular Vesicles in Liver Diseases: Meeting Report from the International Liver Congress 2018

Extracellular vesicles (EVs) are small and heterogeneous membrane-bound structures released by cells and found in all biological fluids. They are effective intercellular communicators, acting on a number of close and/or distant target cells. EV cargo may reflect the cell of origin as well as the specific stress that induces their formation and release. They transport a variety of bioactive molecules, including messenger RNA, noncoding RNAs, proteins, lipids, and metabolites, that can be transferred among cells, regulating various cell responses. Alteration in the concentration and composition of EVs in biological fluids is a typical hallmark of pathologies in different liver diseases. Circulating EVs can serve as biomarkers or as messengers following uptake by other cells. This review is a meeting report from the International Liver Congress 2018 (European Association for the Study of the Liver) celebrated in Paris (Symposium: Extracellular vesicles and signal transmission) that discusses the role of EVs in several liver diseases, highlighting their potential value as disease biomarkers and therapeutic opportunities

Neutrophils induce paracrine telomere dysfunction and senescence in ROS‐dependent manner

Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro-inflammatory phenotype, thought to contribute to aging and age-related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age-related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood. Here, we show that telomeres in non-immune cells are highly susceptible to oxidative damage caused by neighboring neutrophils. Neutrophils cause telomere dysfunction both in vitro and ex vivo in a ROS-dependent manner. In a mouse model of acute liver injury, depletion of neutrophils reduces telomere dysfunction and senescence. Finally, we show that senescent cells mediate the recruitment of neutrophils to the aged liver and propose that this may be a mechanism by which senescence spreads to surrounding cells. Our results suggest that interventions that counteract neutrophil-induced senescence may be beneficial during aging and age-related disease

Death Receptor-Mediated Cell Death and Proinflammatory Signaling in Nonalcoholic SteatohepatitisSummary

Nonalcoholic fatty liver disease (NAFLD) is becoming a public health problem worldwide. A subset of patients develop an inflammatory disease, nonalcoholic steatohepatitis (NASH), characterized by steatosis, hepatocellular death, macrophage and neutrophil accumulation, and varying stages of fibrosis. Hepatocyte cell death triggers the cellular inflammatory response, therefore reducing cell death may be salutary in the steatohepatitis disease process. Recently, a better understanding of hepatocyte apoptosis in NASH has been obtained and new information regarding other cell death modes such as necroptosis and pyroptosis has been reported. Hepatocyte lipotoxicity is often triggered by death receptors. In addition to causing apoptosis, death receptors have been shown to mediate proinflammatory signaling, suggesting that apoptosis in this context is not an immunologically silent process. Here, we review recent developments in our understanding of hepatocyte cell death by death receptors and its mechanistic link to inflammation in NASH. We emphasize how proapoptotic signaling by death receptors may induce the release of proinflammatory extracellular vesicles, thereby recruiting and activating macrophages and promoting the steatohepatitis process. Potential therapeutic strategies are discussed based on this evolving information. Keywords: Apoptosis, Caspase Inhibitor, Cell Death, Death Receptors, Exosomes, Extracellular Vesicles, Fibrosis, Inflammation, Inflammasome, Microvesicles, Necroptosis, Pyroptosi