Lipidomic analysis to identify markers of the beneficial effects of Pioglitazone treatment on fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease that starting from hepatic fat accumulation (NAFL) can progress into more severe forms, i.e., non-alcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma. The derangement in lipid metabolism, either synthesis and accumulation of hepatic TG and secretion of lipotoxic compounds, e.g., ceramides, drives the progression of NAFLD to more severe forms. The prevalence of NAFLD is estimated to be 25% in the general population but increases to more than 55% in subjects with type 2 diabetes. It is therefore important to study the impact antidiabetic drugs on the indexes of NAFLD and the lipidomic profile. Among the most commonly used diabetes medications are metformin (MET) and sulfonylureas (SUL). The PPAR gamma agonist pioglitazone (PIO) is the most suitable antidiabetic treatment to reduce lipotoxicity and glucotoxicity since it significantly reduces hyperglycemia and peripheral lipolysis promoting the increase of subcutaneous adipose tissue but significantly reducing visceral fat and liver steatosis. However, not many studies compared the effects of PIO vs sulphonylurea (SUL) on adipose tissue insulin resistance, lipid composition and metabolism and scores of NAFLD in patients with type 2 diabetes. Thus, the goal of my thesis was to study the impact of hepatic steatosis of metabolic origin (NAFLD / MAFLD) on the circulating lipidome in a population of subjects with type 2 diabetes treated with metformin but with poor glycemic control and then study the metabolic effects of the correction of glycemic control by adding pioglitazone or sulfonylurea; in particular I have investigated the effects on NAFLD / NASH scores, on insulin resistance indices and on the components of the lipidomic profile. The analyses were performed in a group of subjects that participated to the “Thiazolidinediones Or Sulfonylureas Cardiovascular Accidents - Intervention Trial” (TOSCA.IT). One-year treatment with pioglitazone even at low dosage significantly improved liver steatosis and inflammation, systemic and adipose tissue insulin resistance in patients with T2D. Only PIO improved the lipidomic profile of subjects with MAFLD at baseline. The beneficial effects of pioglitazone on NAFLD/MAFLD were independent of blood glucose control. To further explore the mechanism of action of pioglitazone i studied the effect of pioglitazone on difference in lipidomic and de novo synthesis in different adipose tissues and liver of mice fed with high sugar diet. Remarkably, pioglitazone induces a reduction of de novo lipogenesis (DNL) and desaturation in mesenteric adipose tissue and triglycerides associated with DNL in liver. In conclusion, by using lipidomics and fluxomics, we demonstrated that pioglitazone, even at low dosage, exerts positive effects on both glucotoxicity and lipotoxicity by ameliorating insulin resistance and inducing a remodelling of adipose tissue depots.