title: Molecular interplay between Δ5/Δ6 desaturases and long-chain fatty acids in the pathogenesis of non-alcoholic steatohepatitis.
abstract: OBJECTIVE
  The mechanisms underlying non-alcoholic steatohepatitis (NASH) are not completely elucidated. In the current study we integrated gene expression profiling of liver biopsies from NASH patients with translational studies in mouse models of steatohepatitis and pharmacological interventions in isolated hepatocytes to identify new molecular targets in NASH.
  
  
  RESULTS
  Using oligonucleotide microarray analysis we identified a significant enrichment of genes involved in the multi-step catalysis of long-chain polyunsaturated fatty acids, namely, Δ-5 desaturase (Δ5D) and Δ6D in NASH. Increased expression of Δ5D and Δ6D at both mRNA and protein level were confirmed in livers from mice with high-fat diet-induced obesity and NASH. Gas chromatography analysis revealed impaired desaturation fluxes toward the ω-6 and ω-3 pathways resulting in increased ω-6 to ω-3 ratio and reduced ω-3 index in human and mouse fatty livers. Restoration of hepatic ω-3 content in transgenic fat-1 mice expressing an ω-3 desaturase, which allows the endogenous conversion of ω-6 into ω-3 fatty acids, produced a significant reduction in hepatic insulin resistance, steatosis, macrophage infiltration, necroinflammation and lipid peroxidation, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were mostly reproduced by feeding obese mice with an exogenous ω-3-enriched diet. A combined Δ5D/Δ6D inhibitor, CP-24879, significantly reduced intracellular lipid accumulation and inflammatory injury in hepatocytes. Interestingly, CP-24879 exhibited superior antisteatotic and anti-inflammatory actions in fat-1 and ω-3-treated hepatocytes.
  
  
  CONCLUSIONS
  These findings indicate that impaired hepatic fatty acid desaturation and unbalanced ω-6 to ω-3 ratio play a role in the pathogenesis of NASH.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clínic-IDIBAPS-Esther Koplowitz Center, , Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: López-Vicario
authors.forename: Ana
authors.initials: A
authors.lastname: González-Périz
authors.forename: Bibiana
authors.initials: B
authors.lastname: Rius
authors.forename: Eva
authors.initials: E
authors.lastname: Morán-Salvador
authors.forename: Verónica
authors.initials: V
authors.lastname: García-Alonso
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Lozano
authors.forename: Ramón
authors.initials: R
authors.lastname: Bataller
authors.forename: Montserrat
authors.initials: M
authors.lastname: Cofán
authors.forename: Jing X
authors.initials: JX
authors.lastname: Kang
authors.forename: Vicente
authors.initials: V
authors.lastname: Arroyo
authors.forename: Joan
authors.initials: J
authors.lastname: Clària
authors.forename: Esther
authors.initials: E
authors.lastname: Titos
mesh_terms: D000818:Animals; D002849:Chromatography, Gas; D000090943:Delta-5 Fatty Acid Desaturase; D004195:Disease Models, Animal; D044943:Fatty Acid Desaturases / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism*; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D050602:Linoleoyl-CoA Desaturase / Q000378:metabolism*; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000090943:Delta-5 Fatty Acid Desaturase; D005231:Fatty Acids, Unsaturated; D044943:Fatty Acid Desaturases; D050602:Linoleoyl-CoA Desaturase
keywords: BASIC SCIENCES; GENE TARGETING; INFLAMMATION; LIPID MEDIATORS; NONALCOHOLIC STEATOHEPATITIS