IDENTIFICATION OF THE LONG NON-CODING RNAs AND THE SIGNALING PATHWAYS INVOLVED IN THE PROTECTIVE EFFECT OF THE GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST EXENDIN-4 ON HEPATIC STEATOSIS

Abstract

Nonalcoholic Fatty Liver Disease (NAFLD) is characterized by lipid accumulation in the hepatocytes without a coexisting etiology of chronic liver diseases, such as medications, excessive alcohol drinking, or viral hepatitis. NAFLD encompasses steatosis, a benign and reversible condition marked by excessive hepatic triglycerides above 5% of the liver’s weight, and the more aggressive non-alcoholic steatohepatitis (NASH), marked by steatosis and the presence of lobular and portal inflammation, and hepatocyte ballooning. NASH can progress to fibrosis, leading to cirrhosis and eventually to hepatocellular carcinoma. NASH is the fastest growing indication for liver transplantation in Western countries. The exact etiology of NAFLD remains elusive. However, obesity, type 2 diabetes (T2D), dyslipidemia, and insulin resistance are its primary drivers. The pathophysiology of NAFLD is complex and implicates alterations in the metabolism of carbohydrates, lipids, proteins, and insulin signaling. There is also evidence for an element of heritability of NAFLD. There is currently no approved pharmacotherapy for NAFLD. Recent research suggests that glucagon-like peptide-1 receptor agonists (GLP1-RAs) are novel NAFLD therapies because they have a positive effect on liver fat accumulation in NAFLD patients. Despite this beneficial effect, however, the underlying molecular mechanisms remain elusive due to the pleiotropic functions of these drugs. Indeed, GLP-1R agonists could reduce the liver fat content by inducing overall weight loss, mainly visceral fat. These medications, however, could possibly improve NAFLD by directly activating the hepatic GLP-1Rs and their downstream signaling pathways, which would modify the pathways for lipid metabolism and reduce the amount of fat in the liver. Given the difficulty of losing weight and mainly maintaining it, attempting to discover novel liver fat-reducing medications independently of weight loss is of critical therapeutic value. Understanding the GLP-1Rs’ protective effect on NAFLD necessitates a deep comprehension of the underlying molecular mechanisms. LncRNAs are a broad family of non-encoding transcribed RNA molecules with a length of more than 200 nucleotides. LncRNAs play a position in a variety of liver processes, including lipid metabolism, inflammation, cell death, and development. . In previous investigations, the expression of LncRNAs was examined for dysregulation and modification in NAFLD, and many LncRNAs, including MALAT1, NEAT1, H19, and CCAT1, were found to be associated with NAFLD. The present thesis looked at the signaling pathways and LncRNAs that are involved in the GLP1RA Exendin-4's anti-steatosis effects.

Date of Award	2022
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences