ApoB siRNA‐induced Liver Steatosis is Resistant to Clearance by the Loss of Fatty Acid Transport Protein 5 (Fatp5)
Open Access
- 9 August 2011
- Vol. 46 (11), 991-1003
- https://doi.org/10.1007/s11745-011-3596-3
Abstract
The association between hypercholesterolemia and elevated serum apolipoprotein B (APOB) has generated interest in APOB as a therapeutic target for patients at risk of developing cardiovascular disease. In the clinic, mipomersen, an antisense oligonucleotide (ASO) APOB inhibitor, was associated with a trend toward increased hepatic triglycerides, and liver steatosis remains a concern. We found that siRNA-mediated knockdown of ApoB led to elevated hepatic triglycerides and liver steatosis in mice engineered to exhibit a human-like lipid profile. Many genes required for fatty acid synthesis were reduced, suggesting that the observed elevation in hepatic triglycerides is maintained by the cell through fatty acid uptake as opposed to fatty acid synthesis. Fatty acid transport protein 5 (Fatp5/Slc27a5) is required for long chain fatty acid (LCFA) uptake and bile acid reconjugation by the liver. Fatp5 knockout mice exhibited lower levels of hepatic triglycerides due to decreased fatty acid uptake, and shRNA-mediated knockdown of Fatp5 protected mice from diet-induced liver steatosis. Here, we evaluated if siRNA-mediated knockdown of Fatp5 was sufficient to alleviate ApoB knockdown-induced steatosis. We determined that, although Fatp5 siRNA treatment was sufficient to increase the proportion of unconjugated bile acids 100-fold, consistent with FATP5's role in bile acid reconjugation, Fatp5 knockdown failed to influence the degree, zonal distribution, or composition of the hepatic triglycerides that accumulated following ApoB siRNA treatment.Keywords
This publication has 42 references indexed in Scilit:
- In vivo D2O labeling to quantify static and dynamic changes in cholesterol and cholesterol esters by high resolution LC/MSJournal of Lipid Research, 2011
- FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetaseAmerican Journal of Physiology-Endocrinology and Metabolism, 2010
- Effect of apolipoprotein-B synthesis inhibition on liver triglyceride content in patients with familial hypercholesterolemiaJournal of Lipid Research, 2010
- Evaluation of Efficacy, Biodistribution, and Inflammation for a Potent siRNA Nanoparticle: Effect of Dexamethasone Co-treatmentMolecular Therapy, 2010
- Update of the LIPID MAPS comprehensive classification system for lipidsJournal of Lipid Research, 2009
- Silencing of Hepatic Fatty Acid Transporter Protein 5 in Vivo Reverses Diet-induced Non-alcoholic Fatty Liver Disease and Improves HyperglycemiaJournal of Biological Chemistry, 2008
- Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytesProceedings of the National Academy of Sciences of the United States of America, 2007
- LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's diseaseProceedings of the National Academy of Sciences of the United States of America, 2006
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001
- A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATIONCanadian Journal of Biochemistry and Physiology, 1959