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Aims: We aimed to evaluate the protective effects of MLKL deletion in mouse model of high fat (HF) diet induced steatosis.
Methods: 8-9 weeks old C57BL/6 wild type (WT) (n=8) and MLKL-KO (n=6) mice were randomly divided into normal chow (NC) and HF diet groups. NC and HF diet was fed for 12 weeks. The body and diet weight were measured weekly. After 12 weeks the animal were sacrificed, serum and liver samples were collected. Liver weight and liver/body weight ratio was calculated. H&E staining was performed and NAS score was evaluated. Epididymal adipose tissue F4/80 IHC was performed. Liver biopsies of NASH patients were evaluated for MLKL expression.
Results: HF diet increased the body and liver weight of the mice. There was no significant difference in body weight of WT and MLKL-KO mice fed on NC and HF diet. MLKL-KO-HF mice only in 12<sup>th</sup> week had significantly reduced body weights as compared to WT-HF mice. Interestingly, MLKL-KO animals fed on both NC and HF diet had increased diet intake as compared to corresponding WT groups. After 12 weeks, MLKL-KO animals had reduced liver weights as compared to corresponding WT groups. Accordingly, HF diet fed MLKL-KO animals had decreased serum AST, ALT and TG contents. H&E staining showed increased steatosis in HF diet fed animals. However, MLKL-KO-HF mice had reduced steatosis and NAS score. Adipose tissue F4/80 IHC showed HF fed MLKL-KO group had decreased macrophage associated crown-like structures as compared to WT-HF group. Human NASH liver biopsies showed significantly increased MLKL expression as compared to the normal liver, signifying MLKL induction in NASH patients.
Conclusions: Targeting MLKL component of necroptosis pathway significantly decreases liver weight, steatosis and the serum markers of hepatic injury without significantly affecting the overall body weight.