The OBJECTIVES of this application are to advance understanding of genetic pathways in hepatic fatty acid (FA) metabolism that influence the development and regression of hepatic steatosis. The BACKGROUND to this proposal is our elucidation of critical gene-environment interactions that underlie the metabolic pathogenesis of hepatic steatosis, a requisite metabolic precursor to nonalcoholic fatty liver disease. In this application we will focus on pathways modulated by tissue-specific deletion of liver fatty acid binding protein (L-Fabp) and microsomal triglyceride transfer protein (Mttp), each of which play a dominant role in hepatic lipid metabolism. Our OVERARCHING HYPOTHESIS is that L- Fabp regulates metabolic trafficking of FA, cholesterol and bile acids and, in concert with Mttp, modulates substrate utilization for lipoprotein secretion versus storage. Our PRELIMINARY DATA demonstrate that L-Fabp-/- mice are protected against hepatic steatosis following a prolonged fast, and against obesity and hepatic steatosis when fed high saturated fat (SF) diets. We further identified kinetic defects in both hepatic and intestinal FA uptake, re-esterification and secretion in L-Fabp-/- mice. Based on these findings, studies in AIM 1 will ask, """"""""How does L-Fabp deletion protect against high SF diet induced obesity and hepatic steatosis?"""""""" Other work demonstrated that FAs promote coordinated transcriptional regulation of hepatic L-Fabp and Mttp. L-Fabp-/- mice demonstrate attenuated hepatic steatosis with pharmacologic inhibition of Mttp, suggesting that FA trafficking via L-Fabp may be a requisite step in their metabolic channeling for storage as well as for utilization in VLDL assembly and secretion. Based on these findings, studies in AIM 2 will ask, """"""""How does L-Fabp interact with Mttp to modulate FA trafficking for VLDL production versus storage and is this mediated in a tissue-specific manner?"""""""" Quantitative trait mapping identified a chromosomal locus colocalizing with L-Fabp, as a positional candidate for gallstone susceptibility in mice. We demonstrate that L-Fabp-/- mice are dramatically more susceptible to lithogenic diet (LD)-induced gallstones compared to C57BL/6 congenic controls with a phenotype including increased serum and hepatic free cholesterol, increased bile acid pool size and decreased fecal bile acid excretion. These findings suggest that LD-fed L-Fabp-/- mice manifest alterations in both hepatic cholesterol metabolism and biliary lipid secretion as well as changes in intestinal bile acid (BA) metabolism. Based on these findings, studies in AIM 3 will ask, """"""""How does L- Fabp deletion predispose to gallstone susceptibility and alter enterohepatic BA and cholesterol flux?"""""""" Taken together, these studies will provide continued insight into the tissue-specific regulation and pathways of FA utilization relevant to both the pathogenesis and reversal of hepatic steatosis, as well as to cholesterol gallstone formation.

Public Health Relevance

While much is known about the clinical features of NAFLD, relatively little is known about the genetic pathways that predict individual susceptibility to high fat diet-induced hepatic steatosis and specifically the metabolic origins and functional compartmentalization/biological significance of the FA species that accumulate. There is also a paucity of information concerning the integrated roles of intestinal and hepatic FA flux, the factors that regulate the metabolic dialog between de novo lipogenesis and utilization of plasma derived FA, and how these different sources of FA substrate influence the balance between storage versus VLDL production and biliary lipid secretion. Our experiments will use novel and unique mutant mouse genetic models to probe distinct metabolic and tissue-specific pathways of FA utilization and elucidate the adaptive mechanisms that influence development and regression of hepatic steatosis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-DKUS-G (03))
Program Officer
Serrano, Jose
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
Newberry, Elizabeth P; Xie, Yan; Kennedy, Susan M et al. (2016) Prevention of hepatic fibrosis with liver microsomal triglyceride transfer protein deletion in Liver fatty acid binding protein null mice. Hepatology :
Carouge, Delphine; Blanc, Valerie; Knoblaugh, Sue E et al. (2016) Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias. Proc Natl Acad Sci U S A 113:E5425-33
Nalbantoglu, ILKe; Blanc, Valerie; Davidson, Nicholas O (2016) Characterization of Colorectal Cancer Development in Apc (min/+) Mice. Methods Mol Biol 1422:309-27
DeBosch, Brian J; Heitmeier, Monique R; Mayer, Allyson L et al. (2016) Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis. Sci Signal 9:ra21
Wang, Shiyu; Park, Shuin; Kodali, Vamsi K et al. (2015) Identification of protein disulfide isomerase 1 as a key isomerase for disulfide bond formation in apolipoprotein B100. Mol Biol Cell 26:594-604
Lin, Yiing; Lin, Shin; Baxter, Melanie D et al. (2015) Novel APC promoter and exon 1B deletion and allelic silencing in three mutation-negative classic familial adenomatous polyposis families. Genome Med 7:42
Schootman, M; Toor, A; Cavazos-Rehg, P et al. (2015) The utility of Google Trends data to examine interest in cancer screening. BMJ Open 5:e006678
Iqbal, Jahangir; Walsh, Meghan T; Hammad, Samar M et al. (2015) Microsomal Triglyceride Transfer Protein Transfers and Determines Plasma Concentrations of Ceramide and Sphingomyelin but Not Glycosylceramide. J Biol Chem 290:25863-75
Newberry, Elizabeth P; Kennedy, Susan; Xie, Yan et al. (2015) Phenotypic divergence in two lines of L-Fabp-/- mice reflects substrain differences and environmental modifiers. Am J Physiol Gastrointest Liver Physiol 309:G648-61
Olfson, Emily; Cottrell, Catherine E; Davidson, Nicholas O et al. (2015) Identification of Medically Actionable Secondary Findings in the 1000 Genomes. PLoS One 10:e0135193

Showing the most recent 10 out of 110 publications