From Bedside to Bench-side: the Clinical, Epidemiological and Molecular Basis for Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) affect 75-100 million U.S. citizens and carries an increased risk for liver, cardiovascular and cancer related morbidity and mortality. Similarly, chronic hepatitis C virus (HCV) infection is a major cause of liver disease and hepatocellular carcinoma (HCC) worldwide. Understanding the clinical, epidemiology and biological causes of NAFLD, with or without HCV, is of utmost importance given the lack of targeted therapies and the large economic burden it places on healthcare. Accordingly, we aimed to identify the clinical and epidemiological factors that affect HCV treatment in the setting of NAFLD and understand the risk of HCC in the NAFLD patients, compared to viral etiologies of HCC. To do so, we utilized the Electronic Medical Records of the Veterans Affairs Health Care System (VA HCS), the largest single-payer health system in the U.S., and UCLA Medical Center, one of the largest tertiary-care liver transplantation centers in the country. To further understand the molecular basis of NAFLD and NASH, we studied liver RNA-sequencing from a cohort of bariatric surgery patients with detailed liver histopathological data. We found that NAFLD does not affect HCV cure and that resolution of HCV leads to improvements in insulin resistance. We also observe that NAFLD HCC can occur in a non-cirrhosis background in 18% of cases and that older Hispanic patients with larger BMIs were more likely to have cirrhosis when diagnosed with NAFLD HCC. Through analysis of our transcriptomics human liver RNA-sequencing, we identify a lipid responsive non-coding gene, OLMALINC, as a novel enhancer RNA (eRNA) in the cis regulation of stearoyl Co-A desature, a key triglyceride gene that has been a therapeutic target in NASH human clinical trials. In this work, we present the clinical and epidemiological phenotypes of NAFLD and identify important associations between insulin resistance, dyslipidemia, and BMI in HCC. Our functional genomics data in statin-users help us identify the first eRNA in lipid metabolism described to date. Bridging the understanding of clinical phenotypes that translate to human-relevant molecular studies is key to elucidating the mechanisms of NAFLD, NASH and HCC