Digital Theses Archive


Tesi etd-03312021-145906

Type of thesis
Importance of the Gut-Liver Axis on Lipid Metabolism: Implications in the Pathogenesis of Obesity-Related Non-Alcoholic Fatty Liver Disease
Scientific disciplinary sector
Istituto di Scienze della Vita - TRANSLATIONAL MEDICINE
relatore Dott.ssa GASTALDELLI, AMALIA
  • GLP-1RA
  • Gut-liver axis
  • Metabolomics
  • Obesity
  • RYGB
  • Tight junction proteins
Exam session start date
It is estimated that Non-Alcoholic Fatty Liver Disease (NAFLD) affects at least one-third of the world&#39;s population and its incidence has been increasing. NAFLD can easily progress to steatohepatitis (NASH) but the pathophysiological mechanisms are still unknown. It has been hypothesized that derangement in the gut-liver axis could be implicated in the development and progression of NAFLD to NASH, involving possible alterations in the release and/or actions of gut hormones (like glucagon-like peptide-1, GLP-1), nutrient absorption, and gut membrane integrity. <br>For this purpose, we aimed to investigate the role of the gut-liver axis in the pathophysiology of NAFLD: specifically, we investigated the effects on hepatic lipid metabolism of GLP-1 receptor agonists (GLP-1RA) or bariatric surgery (Roux-en-Y gastric bypass, RYGB) in non-diabetic subjects with morbid obesity and NAFLD and the changes in gut integrity after high-fat high-sugar diet in an animal model of NAFLD.<br>As of today, weight loss by diet/exercise or bariatric surgery in subjects with morbid obesity is the only suggested treatment for NAFLD since there is no pharmacological treatment approved. GLP-1 receptor agonists (GLP-1RA) are approved for the treatment of obesity and diabetic hyperglycemia but have been shown promising effects also for the amelioration of NAFLD/NASH. However, the mechanisms accountable for their action have not been completely elucidated. <br>After GLP-1RA exenatide treatment, we observed only mild changes in fasting glucose, amino acid and lipid concentrations despite weight loss, but a significant reduction in the postprandial lipidomic profile, specifically in triacylglycerols (TAG), dihydroceramides (DHC), and lysophosphatidylcholine (LPC). The reductions in TAG were not followed by changes in apolipoprotein B, which suggests increased TAG clearance rather than decreased lipoprotein production.<br>After Roux-en-Y gastric bypass, we observed a decrease in fasting FFA because of a decrease in palmitic and oleic acid, in total plasma diacylglycerols (DAG) and TAG, but the most striking result was the reduction in saturated fatty acids within lipid classes DAG, TAG, LPC and phosphatidylcholine (PC), together with a reduction in branched-chain, glucogenic, ketogenic and essential amino acids and GSG index, a marker of severity of liver disease.<br>In mice, high-fat plus high-sugar diet (HFHS) for 18 weeks led to the development of severe steatosis with no fibrosis-associated increase in body weight. Hepatic tight junction proteins occludin and tricellulin were reduced after HFHS while there was no change in intestinal tight junctions. Expression levels of zonulin, a modulator of intestinal permeability, were not changed after HFHS diet neither in the intestine nor in the liver, which rules out zonulin as a mediator in tight junction-associated changes.<br>Overall, these results point out the importance of the gut-liver axis in the development and progression of NAFLD: 1) the GLP-1RA exenatide exerts its effects mainly by decreasing postprandial triglycerides; 2) RYGB induces important changes in the gut-liver axis with important lipid remodelling associated with a decrease in the secretion of saturated fatty acids; 3) finally, in a rodent model of NAFLD the HFHS diet alters the integrity of hepatocytes but not of the intestine, possibly aggravating the liver condition.