Modulation of hepatic lipid content by Caspase 8 in non-alcoholic steatohepatitis

Aims: Caspase 8, an initiator caspase, plays a crucial role in the induction of apoptosis. Increased apoptotic cell death is a prominent feature of non-alcoholic steatohepatitis (NASH) in humans and animal models. Therefore modulating Caspase 8 activity seems an attractive experimental approach in the treatment of NASH. However, it is essential to identify the mechanisms of Caspase 8 activation and their substrate requirements in order to develop effective inhibitors. Aim: To dissect the role of hepatocyte Caspase 8 (Casp8^Δhepa ) in a murine model of NASH. Methods: We generated Casp8^Δhepa knockout mice. Animals were fed with a methionine-choline-deficient (MCD) diet for 10 weeks. Liver damage was measured by ALT/AST in serum, H/E, TUNEL in liver samples and liver infiltration was assessed by FACS. Results: Casp8^Δhepa mutant mice showed a decreased rate of apoptosis associated with a significantly lower hepatic triglyceride storage and free fatty acid content. Oxidative stress, a key mechanism in the development of NASH, was significantly reduced in Casp8^Δhepa mice. Body composition and metabolic features such as glucose and diabetes development were similar to wild-type levels. Conclusion: Our results suggest that selective ablation of caspase–8 in hepatocytes ameliorate the development of NASH by modulating hepatic lipid storage. The decreased fibrogenesis and hepatic triglyceride storage observed in our study may be directly related to caspase–8 deficiency or, in turn, be a secondary consequence to the altered lipid metabolism status. Our results demonstrate that modulation of caspase–8 activity represents an attractive target for future therapy in the treatment of patients with NASH.

Caspase8 Apoptosis NASH MCD-diet