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.

Fig. 1

Metabolic cross-talk and apoptosis in the progression of obesity and NAFLD/NASH. In obesity, excessive fat accumulation results in overexpansion of adipose tissue, resulting in adipocyte cell death which promotes inflammatory macrophage infiltration and adipose/metabolic dysfunction. Increases in circulating FFA from obese adipose tissue and/or from diet contribute to the excessive accumulation of lipids in the liver and development of NAFLD. Release of inflammatory cytokines from adipose tissue further contributes to liver inflammation, metabolic dysfunction and hepatocyte cell death. Progression of NAFLD to NASH to more severe NASH involves marked increases in hepatocyte apoptosis, resulting in hepatic stellate activation, collagen deposition, scarring and fibrosis. Abbreviations: FFA free fatty acids, HCC hepatocellular carcinoma, HSC hepatic stellate cell, IL interleukin, NAFLD nonalcoholic fatty liver disease, NASH nonalcoholic steatohepatitis, TNF tumour necrosis factor

Fig. 2

Apoptotic pathways in metabolic disease. Caspase-dependent extrinsic and intrinsic apoptotic pathways are induced in response to increases in circulating FFAs, cytokines and intracellular accumulation of toxic lipid species/FFA via increases in mitochondrial dysfunction and ER stress. Extrinsic apoptosis mainly involves activation of the initiator caspase-8, followed by activation of executioner caspases and/or cleavage of Bid, followed by induction of MOMP and subsequent executioner caspase activation. Intrinsic apoptotic pathways can occur via many pathways involving caspase-dependent and independent pathways. Upstream of the MOMP, caspase-2 is activated in response to stress-induced signals including ROS. Precise mechanisms of apoptotic pathways in metabolic disease are still unknown. Abbreviations: ER endoplasmic reticulum, FFA free fatty acids, MOMP mitochondria outer membrane permeabilisation, TNF tumour necrosis factor, TRAIL TNF-related apoptosis-inducing ligand, ROS reactive oxygen species