Document Detail


CYP4F3B Expression is Associated with Differentiation of HepaRG Human Hepatocytes and Unaffected by Fatty Acid Overload.
MedLine Citation:
PMID:  21778351     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Fatty acid microsomal ω-oxidation involves CYP450 enzymes. Some of them belonging to the CYP4F3 family are mainly expressed in the liver making this organ a major player in energy homeostasis and lipid metabolism. To study this important regulation pathway, we used HepaRG cells which gradually undergo a complete differentiation process. Even at the early stage of the differentiation process, CYP4F3B generated by alternative splicing of the CYP4F3 gene represented the prevalent isoform in HepaRG cells as in the liver. Its increasing expression associated with hepatocyte differentiation status suggested a hepatic-specific control of this isoform. As in liver microsomes, the catalytic hydroxylation of the CYP4F3B substrate [1-14C]Z9(10)-epoxystearic acid led to major production of 18-hydroxy-Z9(10)-epoxystearic acid. When treated with saturated, monounsaturated or polyunsaturated fatty acids, CYP4F3B and CYP4A11 expression remained unchanged while CYP4F2 and CYP4F12 expression were transiently up-regulated. A 24 hours exposure of differentiated HepaRG cells to various polyunsaturated fatty acids and derivatives induced microvesicular steatosis, down-regulation of lipid metabolism gene regulators such as SREBP-1c, FAS, PPARγ, PPARα and decreased expression of glucose-dependent metabolism genes which could limit de novo lipogenesis. Docosahexaenoic acid appeared to be the most effective compound. These results suggest that a PPARα independent pathway could participate to limit lipogenesis and emphasize the role of hepatocytes in fatty acids ω-hydroxylation pathway. They also give insights on the use of HepaRG hepatocytes to open new avenues of investigations on factors mediating the lipid metabolic pathway and finding new hypolipidemic molecules.
Authors:
Stephanie Madec; Virginie Cerec; Emmanuelle Plee-Gautier; Joseph Antoun; Denise Glaise; Jean-Pierre Salaun; Christiane Guguen-Guillouzo; Anne Corlu
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-7-21
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  -     ISSN:  1521-009X     ISO Abbreviation:  -     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-7-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1 CNRS UMR 7139;
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