Diet switch and omega-3 hydroxy-fatty acids display differential hepatoprotective effects in an obesity/nonalcoholic fatty liver disease model in mice

Abstract

AIMTo study the effect of 18-hydroxy-eicosapentaenoic acid (18-HEPE) and 17-hydroxy-docosahexaenoic acid (17-HDHA) in a murine model of obesity/nonalcoholic fatty liver disease.METHODSC57BL/6 mice were fed with standard chow diet (CD) or high-fat, fructose-enriched diet (HFD) for 16 wk. Then, three groups were treated for 14 d with either, diet switch (HFD for CD), 18-HEPE, or 17-HDHA. Weight and fasting glucose were recorded on a weekly basis. Insulin tolerance test was performed at the end of treatment. Histological analysis (HE and Masson’s trichrome stain) and determination of serum insulin, glucagon, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide, adiponectin and resistin were carried out as well as liver proteins by western blot.RESULTSMice treated with hydroxy-fatty acids 18-HEPE and 17-HDHA displayed no weight loss or improved insulin sensitivity. However, these mice groups showed a significant amelioration on serum GLP-1, adiponectin and resistin levels. Also, a significant reduction on inflammatory infiltrate was observed at both portal and lobular zones. Furthermore, up-regulation of PPARα/γ protein levels was observed in liver tissue and it was associated with decreased levels of NF-κB also determined by western blot analysis. On the other hand, diet switch regimen resulted in a marked improvement in most parameters including: weight loss, increased insulin sensitivity, decreased steatosis, restored levels of insulin, glucagon, leptin, adiponectin and resistin. However, no significant changes were observed regarding inflammatory infiltrate in this last group.CONCLUSION18-HEPE and 17-HDHA differentially exert hepatoprotective effects through up-regulation of nuclear receptors PPARα/γ and amelioration of serum adipokines profile.

Impact of intravenous fish oil on omega‐3 fatty acids and their derived lipid metabolites in patients with parenteral nutrition

“…Additionally, 14‐HDHA, 17‐HDHA, 15‐HEPE, and 18‐HEPE, which could be the precursors and/or pathway indicators 10 of the resolvin and protectin families of SPMs, were also significantly increased after the introduction of fish oil in PN, raising the possibility that the enhanced formation of 17‐HDHA and 18‐HEPE may improve liver function and dampen inflammation in our patients receiving PN, similar to their protective role in animal studies 40,41 . 18‐HEPE was recently shown to be metabolized by different human LOX isoforms to different resolving products 42 .…”

“…20 Additionally, 14-HDHA, 17-HDHA, 15-HEPE, and 18-HEPE, which could be the precursors and/or pathway indicators 10 of the resolvin and protectin families of SPMs, were also significantly increased after the introduction of fish oil in PN, raising the possibility that the enhanced formation of 17-HDHA and 18-HEPE may improve liver function and dampen inflammation in our patients receiving PN, similar to their protective role in animal studies. 40,41 18-HEPE was recently shown to be metabolized by different human LOX isoforms to different resolving products. 42 However, within the limitations of our analysis, we were not able to detect dihydroxy and trihydroxy SPMs such as maresin-1, resolvin D1 (RvD1), RvD3, RvD5, and RvE1, which might reflect differences in methodology, as discussed in a recent review in this field.…”

TLCD1 and TLCD2 regulate cellular phosphatidylethanolamine composition and promote the progression of non-alcoholic steatohepatitis

“…As the PE species containing eicosapentaenoic acid (EPA, 20:5) were reduced in Tlcd1/2 DKO livers compared to controls on a chow diet (Supplementary Fig. 1e ), it is plausible that some EPA-derived eicosanoid species that we were not able to measure, such as 18-HEPE 39 , could have altered hepatic abundance in Tlcd1/2 DKO animals. Similarly, the livers of WD-fed Tlcd1/2 DKO mice had increased levels of arachidonic acid-containing PC and PE species compared to controls (Supplementary Fig.…”

Effect of ω-3 Polyunsaturated Fatty Acids-Derived Bioactive Lipids on Metabolic Disorders

“…Adipose tissue, as an endocrine tissue, can affect other tissue functions by secreting cytokines. MaR1, 18-HEPE, 17-HDHA, RvD1, and PD1 could increase adiponectin level ( Gonzalez-Periz et al, 2009 ; Hellmann et al, 2011 ; Rius et al, 2014 ; Martinez-Fernandez et al, 2017 ; Rodriguez-Echevarria et al, 2018 ). Adiponectin is an adipose-derived cytokine, one of the most abundant proteins in circulation ( Wang et al, 2010 ).…”

“…18-HEPE and 17-HDHA could improve HFD-induced hepatic steatosis. Also, 18-HEPE and 17-HDHA increased adiponectin level in HFD mouse ( Rodriguez-Echevarria et al, 2018 ). However, whether the beneficial effects of 18-HEPE and 17-HDHA depend on adiponectin need further studies.…”