Thursday, December 26, 2024
12/26/2024
ABSTRACT The non-alcoholic fatty liver disease (NAFLD) spectrum is now the most common cause of liver diseases, and responsible for the biggest proportion of liver transplants. The liver is a central hub that coordinately regulates the metabolism of many nutrients, including lipids. The liver is not designed for long-term storage lipids, instead acting as a distributor of lipids with high short-term storage capacity. Long-term lipid accumulation in the liver, in the form of triglycerides causes steatosis which can progress to non-alcoholic steatohepatitis (NASH), both of which are part of the NAFLD spectrum. Identification of the molecular mechanisms of pathways that control lipid metabolism, both systemic and liver specific are essential for the discovery of disease-preventing therapeutic targets. Bile acids are both signaling molecules and detergents that facilitate lipid absorption in the gut. While much has been studied in recent years about bile acid signaling, the role of bile acids as detergents that facilitate the absorption of different fatty acids has been less well studied. We recently showed activation of the bile acid receptor FXR reduces liver lipid accumulation in part due to lowering of bile acid-mediated lipid absorption. To determine how bile acids alter the absorption of different fatty acids, we have developed and validated a novel AAV-CRISPR strategy to disrupt specific bile acid metabolism genes exclusively in the liver. Using these tools, we show that specific modulations in the total amount and/or composition of bile acids has profound effects on liver steatosis. To measure lipid absorption quantitatively and accurately, we have established a non-invasive mass spectrometry-based approach to measure the absorption of different dietary fatty acids in the intestine in vivo. We have also developed complimentary imaging modalities to visualize lipids in the intestine. Using these assays, we have shown that modulating bile acids dramatically reduces lipid absorption but retain preferential absorption of polyunsaturated fatty acids. These changes contrast with inhibition of lipases in the gut (using Orlistat) which reduced the absorption of all fatty acids. Here, we have designed two specific aims utilizing a combination of in vivo and in vitro systems to test the hypothesis targeting bile acids results in specific and beneficial changes in lipid absorption that are protective against NAFLD or are pathogenic and drive liver fibrosis. Completion of these studies will further the understanding of the role of bile acids as detergents, implicate bile acid metabolism as an important contributor in the pathogenesis of NAFLD/NASH, and potentially establish new therapeutic strategies to target NAFLD.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).