PPARα-activation results in enhanced carnitine biosynthesis and OCTN2-mediated hepatic carnitine accumulation

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Abstract

In fasted rodents hepatic carnitine concentration increases considerably which is not observed in PPARα−/− mice, indicating that PPARα is involved in carnitine homeostasis. To investigate the mechanisms underlying the PPARα-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 PPARα−/− mice. Here we show that both enhancement of carnitine biosynthesis (due to increased γ-butyrobetaine dioxygenase activity), extra-hepatic γ-butyrobetaine synthesis and increased hepatic carnitine import (OCTN2 expression) contributes to the increased hepatic carnitine levels after fasting and that these processes are PPARα-dependent.

Abbreviations

PPARα
Peroxisome proliferator activated receptor α
TML
6-N-trimethyllysine
TMLD
6-N-trimethyllysine dioxygenase
HTML
3-hydroxy-6-N-trimethyllysine
TMABA
4-trimethylaminobutyraldehyde
TMABA-DH
4-trimethylaminobutyraldehyde dehydrogenase
γ-BB
4-trimethylaminobutyric acid
γ-BBD
4-trimethylaminobutyric acid dioxygenase

Keywords

Carnitine
PPARα
Carnitine biosynthesis
OCTN2
γ-butyrobetaine dioxygenase
fasting

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