Myristic acid increases dihydroceramide Δ4-desaturase 1 (DES1) activity in cultured rat hepatocytes.
2012
Dihydroceramide Δ4-desaturase 1 (DES1) catalyzes the last step of the de novo
ceramidebiosynthesis, which consists of the introduction of a trans Δ4-double bond in the carbon chain of the dihydroceramide. It was previously observed that
myristic acidbinds DES1 through N-
myristoylation. This N-terminal modification significantly increased the activity of the recombinant DES1 in COS-7 cells and targeted part of the enzyme initially present in the
endoplasmic reticulumto the mitochondrial outer membrane, leading to an increase in
ceramidelevels. Since these results were obtained in a recombinant COS-7 cell model with high expression of rat DES1, the purpose of the present study was to investigate if the native DES1 enzyme was really upregulated by its N-
myristoylationin cultured rat hepatocytes. We first showed that DES1 was the main
dihydroceramide desaturaseisoform expressed in rat hepatocytes. In this model, the wild-type
myristoylablerecombinant form of rat DES1 was found in both the
endoplasmic reticulumand the mitochondria whereas the mutated non-
myristoylablerecombinant form (N-terminal glycine replaced by an alanine) was almost exclusively localized in the
endoplasmic reticulum, which evidenced the importance of the
myristoylation. Then, we showed that compared to other fatty acids,
myristic acidwas the only one to increase native DES1 activity, in both total cell lysates and mitochondrial fractions. The
myristic acid-associated increase in DES1 activity was not linked to elevated mRNA or protein expression but more likely to its N-terminal
myristoylation. Finally, the
myristic acid-associated increase in DES1 activity slightly enhanced the number of apoptotic cells.
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