Molecular interplay between Δ5/Δ6 desaturases and long-chain fatty acids in the pathogenesis of non-alcoholic steatohepatitis

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. Design and 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, -5 desaturase (5D) and 6D in NASH. Increased expression of 5D and 6D 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 -6 and -3 pathways resulting in increased -6 to -3 ratio and reduced -3 index in human and mouse fatty livers. Restoration of hepatic -3 content in transgenic fat-1 mice expressing an -3 desaturase, which allows the endogenous conversion of -6 into -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 -3-enriched diet. A combined 5D/6D 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 -3-treated hepatocytes. Conclusions These findings indicate that impaired hepatic fatty acid desaturation and unbalanced -6 to -3 ratio play a role in the pathogenesis of NASH.