Role of hepatocyte mitochondrial dysfunction in NAFLD onset and progression – IMHOTEP

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in industrialized countries, whose incidence is rapidly expanding worldwide. NAFLD is a frequent comorbidity of type 2 diabetes and obesity with its prevalence evaluated at ~30% in the general population and 80% among obese people. NAFLD encompasses a spectrum of pathologies ranging from simple steatosis characterized by lipid accumulation in hepatocytes, to non-alcoholic steatohepatitis (NASH), whose hallmarks are inflammation and fibrogenesis, which can further progress to cirrhosis and hepato-cellular carcinoma (HCC), the deadliest form of liver cancer.
Considerable efforts have been made in recent decades to better understand the mechanisms of NAFLD progression and therapeutic targets that might subsequently alleviate the burden of this spectrum of pathologies. The progression of NAFLD is currently explained by a “multiple parallel-hit” hypothesis, which implicates the synergistic and concerted action of multiple events originating from various liver cell types, such as the development of steatosis and free fatty acid overload. In hepatocytes, oxidative stress and mitochondrial dysfunction have been suggested to contribute to hepatocyte damage and death, tissue inflammation and fibrosis. Mitochondria are multifunctional organelles that control the generation of cellular energy through oxidative phosphorylation (OXPHOS), the maintenance and generation of reactive oxygen species, calcium buffering, programmed cell death (PCD), and inflammation. Compelling evidence implicates mitochondria in the appearance and progression of NAFLD and liver dysfunction, but there is considerable controversy and confusion regarding the nature of the specific mitochondrial functions that are causally linked to diet-induced liver dysfunction and NAFLD.
Our project aims at defining the respective contributions of OXPHOS and PCD in the onset of steatosis, and at exploring whether these enhanced mitochondrial functions protect against NAFLD progression using a novel mouse model deleted for the mitochondrial fission process 1 protein Mtfp1. In humans, MTFP1 has recently emerged as a regulator of mitochondrial dynamics and has been associated to the recurrence risk and patient survival in HCC. By surveying liver biopsies of human patients with NAFLD, we found a positive correlation between Mtfp1 expression and the activity score reflecting on hepatocyte ballooning and inflammation, two histological characteristics of NASH. In mice, we discovered that deletion of Mtfp1 in hepatocytes protects against diet-induced hepatic steatosis and PCD. Mtfp1 KO mice exhibit an upregulation of OXPHOS complexes and mitochondrial respiration and increased resistance to the opening of the mitochondrial permeability transition pore (mPTP), conferring protection against apoptotic liver damage in vivo and in primary hepatocytes. Now, we seek to understand the breadth of protection that Mtfp1 ablation can confer against NAFLD progression by investigating the transition from steatosis to NASH. We will investigate the underlying molecular mechanisms governed by Mtfp1 using multidisciplinary approaches involving integrative physiology, genetics, biochemistry, and cell biology in vivo and ex vivo to dissect the contribution of enhanced OXPHOS from mPTP resistance in NAFLD progression. In humans, we will use patient-derived hepatocytes and precision-cut liver slices to functionally test the importance of MTPF1 for hepatic steatosis and NAFLD progression.
In sum, the Imhotep project will define the relevance of Mtfp1 in the safeguarding against NAFLD progression and will provide functional insights into the relevance of mitochondrial activity for hepatocyte function in health and disease.