Caspases in metabolic disease and their therapeutic potential

Abstract

Caspases, a family of cysteine-dependent aspartate-specific proteases, are central to the maintenance of cellular and organismal homoeostasis by functioning as key mediators of the inflammatory response and/or apoptosis. Both metabolic inflammation and apoptosis play a central role in the pathogenesis of metabolic disease such as obesity and the progression of nonalcoholic steatohepatisis (NASH) to more severe liver disease. Obesity and nonalcoholic fatty liver disease (NAFLD) are the leading global health challenges associated with the development of numerous comorbidities including insulin resistance, type-2 diabetes and early mortality. Despite the high prevalence, current treatment strategies including lifestyle, dietary, pharmaceutical and surgical interventions, are often limited in their efficacy to manage or treat obesity, and there are currently no clinical therapies for NAFLD/NASH. As mediators of inflammation and cell death, caspases are attractive therapeutic targets for the treatment of these metabolic diseases. As such, pan-caspase inhibitors that act by blocking apoptosis have reached phase I/II clinical trials in severe liver disease. However, there is still a lack of knowledge of the specific and differential functions of individual caspases. In addition, cross-talk between alternate cell death pathways is a growing concern for long-term caspase inhibition. Evidence is emerging of the important cell-death-independent, non-apoptotic functions of caspases in metabolic homoeostasis that may be of therapeutic value. Here, we review the current evidence for roles of caspases in metabolic disease and discuss their potential targeting as a therapeutic strategy.

Absence of the Caspases 1/11 Modulates Liver Global Lipid Profile and Gut Microbiota in High-Fat-Diet-Induced Obese Mice

“…Since caspase 1 is an important regulator for the maturation of these cytokines during inflammasome activation, many studies have started to investigate the role of this protein in the development of obesity, NAFLD, and other metabolic disorders. The precise role of caspase-1 during metabolic inflammation is still unclear and remains a little controversial due to contrasting results obtained with the use of knockout mice (28). Previous work from Wang et al (13) and Kimura et al (29) found that caspase-1 knockout mice increased their body weight under HFD compared to WT mice.…”

Hepatic signalling disruption by pollutant Polychlorinated biphenyls in steatohepatitis

“…Also CK2β is downregulated with Aroclor exposure, as well, which has been shown to be required for the tetrameric formation [38]. CK2 is the main regulator CASP3 phosphorylation that negatively regulates apoptosis through prevention of CASP3 self-cleavage and activation [37, 40, 42]. …”

“…CASP3 is a measure of apoptotic cell death that can be due to intrinsic or extrinsic activation [37, 42]. Apoptosis is a programmed form of cell death that is often considered non-inflammatory, as opposed to necrosis [43].…”

Epidermal growth factor receptor (EGFR) inhibition by polychlorinated biphenyls contributes to non-alcoholic fatty liver disease (NAFLD).

“…Also CK2b is downregulated with Aroclor exposure, as well, which has been shown to be required for the tetrameric formation (163). CK2 is the main regulator CASP3 phosphorylation that negatively regulates apoptosis through prevention of CASP3 self-cleavage and activation (167,168,170).…”

“…CASP3 is a measure of apoptotic cell death that can be due to intrinsic or extrinsic activation (167,170). Apoptosis is a programmed form of cell death that is often considered noninflammatory, as opposed to necrosis (171).…”