Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia.
Non-alcoholic fatty liver disease is a serious health problem linked to obesity and type 2 diabetes. To investigate the biological outcome and therapeutic potential of hepatic fatty acid uptake inhibition, we utilized an adeno-associated virus-mediated RNA interference technique to knock down the expression of hepatic fatty acid transport protein 5 in vivo prior to or after establishing non-alcoholic fatty liver disease in mice. Using this approach, we demonstrate here the ability to achieve specific, non-toxic, and persistent knockdown of fatty acid transport protein 5 in mouse livers from a single adeno-associated virus injection, resulting in a marked reduction of hepatic dietary fatty acid uptake, reduced caloric uptake, and concomitant protection from diet-induced non-alcoholic fatty liver disease. Importantly, knockdown of fatty acid transport protein 5 was also able to reverse already established non-alcoholic fatty liver disease, resulting in significantly improved whole-body glucose homeostasis. Thus, continued activity of hepatic fatty acid transport protein 5 is required to sustain caloric uptake and fatty acid flux into the liver during high fat feeding and may present a novel avenue for the treatment of non-alcoholic fatty liver disease.
Doege
Holger
H
Palo Alto Medical Foundation Research Institute, Palo Alto, California 94301, USA.
Grimm
Dirk
D
Falcon
Alaric
A
Tsang
Bernice
B
Storm
Theresa A
TA
Xu
Hui
H
Ortegon
Angelica M
AM
Kazantzis
Melissa
M
Kay
Mark A
MA
Stahl
Andreas
A
D000818:Animals; D002460:Cell Line; D004032:Diet; D004041:Dietary Fats / Q000378:metabolism; D050612:Fatty Acid Transport Proteins / Q000172:deficiency* / Q000235:genetics*; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism
D004041:Dietary Fats; D050612:Fatty Acid Transport Proteins; D034741:RNA, Small Interfering; C113098:Slc27a5 protein, mouse