Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis

Abstract

Objective Caspase-2 is an initiator caspase involved in multiple apoptotic pathways, particularly in response to specific intracellular stressors (eg. DNA damage, ER stress). We recently reported that caspase-2 was pivotal for the induction of cell death triggered by excessive intracellular accumulation of long chain fatty acids, a response known as lipoapoptosis. The liver is particularly susceptible to lipid-induced damage, explaining the pandemic status of non-alcoholic fatty liver disease (NAFLD). Progression from NAFLD to non-alcoholic steatohepatitis (NASH) results, in part, from hepatocyte apoptosis and consequential paracrine-mediated fibrogenesis. We evaluated the hypothesis that caspase-2 promotes NASH-related cirrhosis. Design Caspase-2 was localized in liver biopsies from NASH patients. Its expression was evaluated in different mouse models of NASH, and outcomes of diet-induced NASH were compared in wild type (WT) and caspase-2 deficient mice. Lipotoxicity was modeled in vitro using hepatocytes derived from WT and caspase-2 deficient mice. Results We showed that caspase-2 is integral to the pathogenesis of NASH-related cirrhosis. Caspase-2 is localized in injured hepatocytes and its expression was markedly up-regulated in patients and animal models of NASH. During lipotoxic stress, caspase-2 deficiency reduced apoptosis, inhibited induction of pro-fibrogenic Hedgehog target genes in mice, and blocked production of Hedgehog ligands in cultured hepatocytes. Conclusion These data point to a critical role for caspase-2 in lipid-induced hepatocyte apoptosis in vivo, for the production of apoptosis-associated fibrogenic factors and in the progression of lipid-induced liver fibrosis. This raises the intriguing possibility that caspase-2 may be a promising therapeutic target to prevent progression to NASH.

Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease

“…Immunohistochemistry (IHC) was done as previously described [17]. Morphometric analysis was done with Metamorph Software (Molecular Devices Corporation) in 20x magnification, 20 fields/sample, and expressed as percent of section stained.…”

The hedgehog pathway in nonalcoholic fatty liver disease

“…Briefly, the Hh pathway has been studied in different animal models of NASH, including genetically obese leptin-deficient ob/ob mice and wild type mice with NASH induced by feeding either diets deficient in methionine and choline or diets enriched with various fats (Fleig et al, 2007; Syn et al, 2009; Hirsova et al, 2013; Machado et al, 2015; Wang et al, 2016). In all models, hepatic Hh pathway activation has been observed consistently.…”

“…In all models, hepatic Hh pathway activation has been observed consistently. Similarly, in human NASH the Hh pathway is activated and the level of pathway activity correlates with the severity of liver damage (as assessed by numbers of ballooned hepatocytes, levels of portal inflammation, markers of liver repair (aka accumulation of progenitor cells and activated myofibroblasts), and fibrosis severity) (Guy et al, 2012; Grzelak et al, 2017; Syn et al, 2009; Machado et al, 2015). …”

“…The number of Shh-expressing hepatocytes correlates with fibrosis severity, and the severity of the ductular reaction (Guy et al, 2012; Machado et al, 2015) which is known to associate with fibrogenesis and carcinogenesis (Richardson et al, 2007; Ye et al, 2014). Once the Hh pathway is activated, it can induce a strong self-perpetuating response.…”

Effect of curcumin on visfatin and zinc-α2-glycoprotein in a rat model of non-alcoholic fatty liver disease

“…Non-alcoholic fatty liver disease (NAFLD) is a group of clinical pathological syndromes, and its disease spectrum includes simple fatty liver disease, non-alcoholic steatohepatitis, and related cirrhosis [1][2][3][4][5] . The pathogenesis of NAFLD is not yet clear but Day's "two-strike" theory is accepted by most scholars.…”