[Cell death mechanisms in non-alcoholic steatohepatitis]. / Les mécanismes de mort cellulaire dans la stéatohépatite non alcoolique.

Continuous cell death associated with inflammation is a key trigger of disease progression notably in chronic liver diseases such as non-alcoholic steatohepatitis (NASH). Apoptosis has been studied as a potential target for reducing cell death in NASH. However, recent studies suggest that caspase inhibition is inefficient to treat NASH patients and may aggravate the disease by redirecting cells to alternative mechanisms of cell death. Alternative forms of lytic cell death have recently been identified and are known to induce strong inflammatory responses due to cell membrane permeabilization. Therefore, controlling lytic cell death modes offers new opportunities for potential therapeutic intervention in NASH. This review summarizes the underlying molecular mechanisms of apoptosis and lytic cell death modes, including necroptosis, pyroptosis and ferroptosis, and discusses their relevance in NASH.

TITLE: Les mécanismes de mort cellulaire dans la stéatohépatite non alcoolique. ABSTRACT: La mort hépatocellulaire chronique et l'inflammation qui en résulte sont des évènements clés dans la progression de la stéatose hépatique non alcoolique (NAFL) vers la stéatohépatite non alcoolique (NASH). La NASH est un état sévère de la maladie qui est associé au développement de la fibrose et qui peut à terme évoluer vers la cirrhose et le cancer du foie. L'apoptose a initialement été étudiée comme cible potentielle pour réduire la mort des hépatocytes dans la NASH. Cependant, des études récentes suggèrent que l'inhibition des caspases est inefficace pour traiter les patients atteints de NASH et pourrait même aggraver la maladie en redirigeant les hépatocytes vers d'autres voies de mort cellulaire. De nouvelles formes de mort cellulaire dites lytiques ont récemment été identifiées et induisent de fortes réponses inflammatoires causées par la perméabilisation des membranes cellulaires. Le contrôle de ces voies de mort lytiques offre par conséquent de nouvelles opportunités thérapeutiques pour traiter la NASH. Cette revue résume les mécanismes moléculaires déclenchant l'apoptose et les voies de mort lytiques, parmi lesquelles la nécroptose, la pyroptose et la ferroptose, et discute de leur pertinence dans la NASH.

Modulatory role of Co-enzyme Q10 on methionine and choline deficient diet-induced non-alcoholic steatohepatitis (NASH) in albino rats.

The present study aimed to evaluate the hepato-protective and neuro-protective activity of Co-enzyme Q10 (CoQ10) on non-alcoholic steatohepatitis (NASH) in albino rats induced by methionine and choline-deficient (MCD) diet. Rats were fed an MCD diet for 8 weeks to induce non-alcoholic steatohepatitis. CoQ10 (10 mg/(kg·day)-1) was orally administered for 2 consecutive weeks. Twenty-four hours after the last dose of the drug, the behavioral test, namely the activity cage test, was performed and the activity counts were recorded. Serum alanine transaminase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, total/direct bilirubin, and albumin were valued to assess liver function. Moreover, hepatic cytokines interleukin-6 as well as its modulator nuclear factor kappa-light-chain-enhancer of activated B cells were determined. In addition, brain biomarkers, viz ammonia, nitric oxide, and brain-derived neurotrophic factor (BDNF), were measured as they are reliable indices to assess brain damage. Histopathological and immunohistochemical examination of brain proliferating cell nuclear antigen in brain and liver tissues were also evaluated. Results revealed that MCD-induced NASH showed impairment in the liver functions with an increase in the liver inflammatory markers. Moreover, NASH resulted in pronounced brain dysfunction as evidenced by hyper-locomotor activity, a decrease in the BDNF level, as well as an increase in the brain nitric oxide and ammonia contents. Oral treatment of MCD-diet-fed rats with CoQ10 for 14 days showed a marked improvement in all the assigned parameters. Finally, it can be concluded that CoQ10 has a hepatoprotective and neuroprotective role in MCD-diet-induced NASH in rats.