A new pathway for reducing liver lipotoxicity bridging non-alcoholic steatohepatitis and atherosclerosis in type 2 diabetes – DETOXING

Nonalcoholic fatty liver disease (NAFLD) is an increasing chronic liver pathology affecting around 25% of the general population in Western countries. NAFLD is a continuum of pathological states ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) which can progress to fibrosis, cirrhosis, end stage liver disease and liver transplantation. Prevalence of NASH is three times more elevated in patients with type 2 diabetes (T2D) and is an independent risk factor for cardiovascular diseases (CVD). Accumulation of lipotoxic lipids such as ceramides in the liver has been reported to play a major role in the development of NASH by promoting insulin resistance, endoplasmic reticulum and oxidative stress and apoptosis in hepatocytes. The capacity of liver to eliminate the excess of ceramides is critical for reducing hepatic lipotoxicity and for protection from NASH.
Our preliminary data lead us to propose that the export of ceramides to high-density lipoproteins (HDL) mediated by the membrane ATP-Binding Cassette G1 (ABCG1) transporter might attenuate hepatic lipotoxicity and reduce the onset of NASH and CVD.
To address this hypothesis, we will investigate the 1). In vitro impact of the cytotoxic ceramide removal by ABCG1 using human hepatocytes and precision-cut liver slices obtained from healthy or NASH livers, 2). In vivo impact of the liver ABCG1 / HDL axis on the development of NASH and atherosclerosis using a unique mouse model exhibiting a “humanized” lipoprotein profile and susceptible to atherosclerosis and 3). Contribution of the liver ABCG1/HDL axis in the liver-heart crosstalk in NASH patients thanks to cohorts of well phenotyped T2D and NAFLD patients. All the experimental tools and cohorts are already available.
This project will help to propose new therapeutic strategies to decrease lipotoxicity in the liver and to reduce both NASH and CVD development in T2D patients.