Crosstalks between insulin signaling and lipidome in steatosis – CRISALIS

Nonalcoholic fatty liver disease (NAFLD) is gaining increasing recognition as a component of the epidemic of obesity. NAFLD is the most common cause of liver dysfunction and affects patients worldwide. The spectrum of NAFLD ranges from simple fatty liver (hepatic steatosis), with benign prognosis, to a potentially progressive form, nonalcoholic steatohepatitis (NASH), which may lead to liver fibrosis and cirrhosis, resulting in increased morbidity and mortality. All features of the metabolic syndrome, including obesity, type 2 diabetes, arterial hypertension, and hyperlipidemia (in the form of elevated triglyceride (TG) levels) are associated with NAFLD/NASH. NAFLD is generally asymptomatic, although a minority of patients may present progressive liver injury with complications of cirrhosis, liver failure, and hepatocellular carcinoma. Despite being potentially severe, little is known about the natural history or prognostic significance of NAFLD. Although diabetes, obesity, and age are recognized risk factors for advanced liver disease, other significant factors leading to progressive liver injury remain to be identified. Interestingly, despite the existing correlation between fatty liver and insulin resistance, it remains unclear whether insulin resistance causes the excessive accumulation of TG in the liver, or whether the increase in TG itself or other lipid intermediates such as diacylglycerols (DAG) and/or ceramides may trigger the development of hepatic or systemic insulin resistance. While some studies support the concept that intrahepatic accumulation of lipids precedes insulin resistance, other reports suggest that hepatic TG may in fact protect the liver from lipotoxicity by buffering the accumulation of fatty acids. Such discrepancy might be explained since different pools of lipids exist within cells and only certain pools regulate insulin signaling. Consistent with such hypothesis, recent results by the members our consortium strongly support that specific fatty acid species may influence hepatic TG storage, insulin signaling and/or inflammation. Therefore, the global aim of our proposal is to better understand the regulation of hepatic fatty acid synthesis and its impact on the detailed lipid profile (lipidome). Using state-of-art technology and key genetically-modified mouse models combined with original nutritional approaches and lipidomic analysis, our project aims at providing new information on the molecular basis of the pathogenesis of NAFLD. Together with the specific skills of each partner we will jointly use molecular biology and lipid biochemistry combined in full force with original nutritional and genetic approaches in vivo to address four issues: i) Role of LXR in steatosis induced by essential fatty acid deficiency, relationship to oxysterol metabolism; ii) Determination of the transcriptional network regulating fatty acid synthesis by deciphering the specific impact of LXR, ChREBP and SREBP-1c respectively on the hepatic lipidome iii) Study the effects of mono-unsaturated fatty acid (and their dependence on StearoylCoA Desaturase SCD1) on insulin resistance and inflammation and lastly, iv) investigate the potential coupling of fatty acid and ceramide synthesis and their influence on membrane signaling.
Altogether, the aim of this program is to provide a better understanding of the different pathways which control fatty acid synthesis and their specific biological significance.