PPAR alpha-activation results in enhanced carnitine biosynthesis and OCTN2-mediated hepatic carnitine accumulation.
In fasted rodents hepatic carnitine concentration increases considerably which is not observed in PPAR alpha-/- mice, indicating that PPAR alpha is involved in carnitine homeostasis. To investigate the mechanisms underlying the PPAR alpha-dependent hepatic carnitine accumulation we measured carnitine biosynthesis enzyme activities, levels of carnitine biosynthesis intermediates, acyl-carnitines and OCTN2 mRNA levels in tissues of untreated, fasted or Wy-14643-treated wild type and PPAR alpha-/- mice. Here we show that both enhancement of carnitine biosynthesis (due to increased gamma-butyrobetaine dioxygenase activity), extra-hepatic gamma-butyrobetaine synthesis and increased hepatic carnitine import (OCTN2 expression) contributes to the increased hepatic carnitine levels after fasting and that these processes are PPAR alpha-dependent.
van Vlies
Naomi
N
Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands.
Ferdinandusse
Sacha
S
Turkenburg
Marjolein
M
Wanders
Ronald J A
RJ
Vaz
Frédéric M
FM
D000818:Animals; D001483:Base Sequence; D002331:Carnitine / Q000096:biosynthesis* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D027701:Organic Cation Transport Proteins / Q000502:physiology*; D047493:PPAR alpha / Q000378:metabolism*; D051381:Rats; D012689:Sequence Homology, Nucleic Acid; D000074058:Solute Carrier Family 22 Member 5; D050563:gamma-Butyrobetaine Dioxygenase / Q000378:metabolism
D027701:Organic Cation Transport Proteins; D047493:PPAR alpha; C492019:Slc22a5 protein, mouse; D000074058:Solute Carrier Family 22 Member 5; D050563:gamma-Butyrobetaine Dioxygenase; D002331:Carnitine