Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia

J Biol Chem. 2008 Aug 8;283(32):22186-92. doi: 10.1074/jbc.M803510200. Epub 2008 Jun 3.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Diet*
  • Dietary Fats / metabolism
  • Fatty Acid Transport Proteins / deficiency*
  • Fatty Acid Transport Proteins / genetics*
  • Fatty Liver / genetics
  • Fatty Liver / metabolism*
  • Gene Silencing*
  • Humans
  • Hyperglycemia / genetics
  • Hyperglycemia / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • RNA, Small Interfering / metabolism

Substances

  • Dietary Fats
  • Fatty Acid Transport Proteins
  • RNA, Small Interfering
  • Slc27a5 protein, mouse