Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis.
OBJECTIVE
Fatty acid transport protein 5 (FATP5/Slc27a5) has been shown to be a multifunctional protein that in vitro increases both uptake of fluorescently labeled long-chain fatty acid (LCFA) analogues and bile acid/coenzyme A ligase activity on overexpression. The aim of this study was to further investigate the diverse roles of FATP5 in vivo.


METHODS
We studied FATP5 expression and localization in liver of C57BL/6 mice in detail. Furthermore, we created a FATP5 knockout mouse model and characterized changes in hepatic lipid metabolism (this report) and bile metabolism (the accompanying report by Hubbard et al).


RESULTS
FATP5 is exclusively expressed by the liver and localized to the basal plasma membrane of hepatocytes, congruent with a role in LCFA uptake from the circulation. Overexpression of FATP5 in mammalian cells increased the uptake of 14C-oleate. Conversely, FATP5 deletion significantly reduced LCFA uptake by hepatocytes isolated from FATP5 knockout animals. Moreover, FATP5 deletion resulted in lower hepatic triglyceride and free fatty acid content despite increased expression of fatty acid synthetase and also caused a redistribution of lipids from liver to other LCFA-metabolizing tissues. Detailed analysis of the hepatic lipom of FATP5 knockout livers showed quantitative and qualitative alterations in line with a decreased uptake of dietary LCFAs and increased de novo synthesis.


CONCLUSIONS
Our findings support the hypothesis that efficient hepatocellular uptake of LCFAs, and thus liver lipid homeostasis in general, is largely a protein-mediated process requiring FATP5. These new insights into the physiological role of FATP5 should lead to an improved understanding of liver function and disease.
Doege
Holger
H
Division of GI/Hepatology, Stanford University School of Medicine, Stanford, California 94301, USA.
Baillie
Rebecca A
RA
Ortegon
Angelica M
AM
Tsang
Bernice
B
Wu
Qiwei
Q
Punreddy
Sandhya
S
Hirsch
David
D
Watson
Nicki
N
Gimeno
Ruth E
RE
Stahl
Andreas
A
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002478:Cells, Cultured; D004041:Dietary Fats / Q000493:pharmacokinetics; D005215:Fasting; D050612:Fatty Acid Transport Proteins / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D005227:Fatty Acids / Q000096:biosynthesis / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D007657:Ketone Bodies / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D014018:Tissue Distribution; D014280:Triglycerides / Q000378:metabolism
D001647:Bile Acids and Salts; D004041:Dietary Fats; D050612:Fatty Acid Transport Proteins; D005227:Fatty Acids; D007657:Ketone Bodies; C113098:Slc27a5 protein, mouse; D014280:Triglycerides