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. 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, 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.

Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis

“…The average gene expression for each of these pathways (with the exception of cholesterol biosynthesis) was significantly elevated (FDR < 5%). Using these same methods, 2 independent studies that evaluated gene expression changes in NASH patients (17,18) were analyzed to benchmark the in vitro transcriptomic signature. Table 1 shows pathway analysis results, including directional pathway regulation in patient biopsies and this in vitro lipotoxic model.…”

Transcriptional regulation of apolipoprotein A-IV by the transcription factor CREBH

“…In this regard, a recent study demonstrated that CREB3, another transmembrane bZIP transcription factor closely related to CREBH, activates apoA-IV transcription upon overexpression ( 46 ). It would GSE48452, GSE37031, and GSE28619) (31)(32)(33)(34). ApoA-IV is a 46 kDa glycoprotein (43 kDa for mouse) that has been implicated in multiple metabolic functions ( 14,35 ).…”

The LATS2 tumor suppressor inhibits SREBP and suppresses hepatic cholesterol accumulation

“…7A, left column). Moreover, analysis of data from a recent study (Lopez-Vicario et al 2014) revealed significantly lower LATS2 mRNA (Fig. 7B) and enrichment of the SREBP2 signature (Fig.…”

“…We compiled a hepatic SREBP2 target gene signature from the data presented in Figure 2, B and C, and Supplemental Fig. S3C (assembled in Supplemental Table S2) and used it to query a series of human liver samples (Ahrens et al 2013;Lopez-Vicario et al 2014;Moylan et al 2014). Importantly, in healthy livers, the SREBP2 signature was highly enriched in cases with low LATS2 expression compared with those with high Figure 6.…”