INCIDENCE AND SEVERITY OF NONALCOHOLIC FATTY LIVER DISEASE ASSOCIATED WITH IMPAIRED LIPID AND GLUCOSE METABOLISM ARE PREDICTED BY SREBF POLYMORPHISM.

Background: Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease, encompasses a histological spectrum, ranging from simple steatosis (SS) to steatosis plus necroinflammation (nonalcoholic steatohepatitis, NASH), which can be differentiated only by liver biopsy. While SS has a benign hepatological course, NASH can progress to end-stage liver disease. Sterol regulatory element-binding factor (SREBF) genes code for key nuclear transcription factors regulating lipid homeostasis: sterol regulatory element binding protein (SREBP)-1c regulates hepatic de novo lipogenesis and insulin sensitivity, while sterol regulatory element-binding factor-2 (SREBF-2) codes for SREBP-2, a master transcriptional regulator of genes involved in cellular cholesterol biosynthesis, uptake, and export. Therefore, SREBF-1c and SREBF-2 may modulate the genetic susceptibility to NAFLD and NASH. Objective. Factors predisposing to non-alcoholic fatty liver disease (NAFLD) and associated cardio-metabolic disorders are unknown. Sterol regulatory element-binding protein (SREBP)-1c and SREBP-2, transcription factors regulating lipogenesis and cholesterol metabolism have been experimentally connected to NAFLD, but no human data exist. In population-based studies, single nucleotide polymorphisms (SNPs) in SREBF-1 gene have been connected to obesity, insulin resistance and T2DM, and the functional SNP rs133291 C/T in the SREBF2 gene has been linked to serum LDL-cholesterol, but there are no human data on the impact of these SNPs on the risk of developing NAFLD and associated metabolic abnormalities. We hypothesized SREBF-1c/2 SNPs may not only predispose not only to NAFLD/NASH, but also affect NAFLD-associated cardio-metabolic risk. We aimed at: 1) prospectively assessing the role of SREBF-1c/2 SNPs in promoting NAFLD development in apparently healthy subjects 2) elucidating mechanisms connecting SREBF-1c/2 to liver injury, glucose and lipid homeostasis in established NAFLD. Methods: We followed-up 165 non-obese nondiabetic participants in a population-based study, without NAFLD/metabolic syndrome, characterized for 2 common SREBF-1c and SREBF-2 polymorphisms, dietary habits, physical activity, adipokines, CRP, and endothelial dysfunction markers. NAFLD developers underwent an OGTT with Minimal Model analysis of glucose homeostasis parameters, and an oral fat tolerance test with measurement of plasma lipoproteins, adipocytes, and hepatocyte apoptosis marker cytokeratin-18 fragments. Results: After 7 years, 29% subjects developed NAFLD and 5% developed diabetes. SREBF-1c and SREBF-2 predicted incident NAFLD; SREBF-2 predicted non-alcoholic steatohepatitis (NASH), diabetes, CRP and endothelial dysfunction markers. In NAFLD, while SREBF-1c predicted histological steatosis and hepatic insulin resistance, SREBF-2 predicted progressive liver histology, hepatic/muscle/adipose insulin resistance, pancreatic -cell dysfunction, and an altered fat tolerance: higher postprandial lipemia, cholesterol enrichment of triglyceride-rich lipoproteins and ox-LDLs, HDL-C reduction, adipokine imbalance (lower adiponectin and higher resistin), and higher cytokeratin-18 fragments. Conclusions: SREBF-2 predisposes to NASH and cardio-metabolic disorders by affecting glucose homeostasis and dietary fat tolerance. We showed polymorphisms in genes coding for nuclear transcription factor SREBP-2 predict incidence and severity of NAFLD and of associated abnormalities in glucose and lipid metabolism and in adipokine response to dietary fat. Our findings may have relevant implications: from a clinical standpoint, SREBF-1/2 SNPs may be used to select NAFLD patients at higher risk of developing progressive liver disease and cardio-metabolic complications for tight monitoring and experimental treatments. Furthermore, future research should verify whether a genetically-mediated maladaptive response to a chronic, daily, repetitive stress like fat ingestion may link chronic overfeeding to obesity and its complications and to assess whether SREBP-2 pathway modulation may prevent cholesterol lipotoxicity in different tissues more effectively than currently available strategies, which selectively target hepatic cholesterol synthesis or intestinal absorption.