Exploring the role of novel candidates in the initiation and progression of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD includes multiple liver injuries, including accumulation of fats (lipids), known as steatosis, liver cell damage combined with liver inflammation (non-alcoholic steatohepatitis (NASH)), and the formation (fibrosis) of scar tissue (also known as cirrhosis). While steatosis and inflammation of the liver are reversible, NASH can also progress to irreversible disease states, such as cirrhosis and liver cancer. NAFLD also increases the risk of atherosclerotic cardiovascular disease (ASCVD) and NAFLD is strongly associated with obesity, insulin resistance, and diabetes. Currently, there are no drugs to treat NAFLD. To treat NAFLD in the future, more knowledge is required about how NAFLD arises and how it develops into NASH and liver cancer. The work in my thesis shows the importance of chronic liver inflammation in the initiation of NAFLD and increasing the risk of ASCVD. We showed that chronic liver inflammation promotes the production of different types of lipids in the liver. We also uncovered that a ‘long non-coding RNA’ (lncRNA), recently associated with the NASH grade, does not play a direct role in the development of NAFLD. However, we found that this lncRNA may contribute to the development of liver cancer in a preclinic mouse model of NAFLD and liver cancer. Finally, we provided more molecular insight into the processes that facilitate absorption of cholesterol in the gut. This knowledge can be used to better understand the wide variation in intestinal absorption of cholesterol in humans.