Omega-3 PUFA modulate lipogenesis, ER stress, and mitochondrial dysfunction markers in NASH - Proteomic and lipidomic insight

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dc.contributor Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP OKADA, Livia Samara dos Reis Rodrigues FMUSP-HC
NOGUEIRA, Monize Aydar
SILVA, Ismael Dale Cotrim Guerreiro da
CORDEIRO, Fernanda Bertucce
ALVES, Venancio Avancini Ferreira FMUSP-HC
PURI, Puneet
dc.identifier.citation CLINICAL NUTRITION, v.37, n.5, p.1474-1484, 2018
dc.identifier.issn 0261-5614
dc.description.abstract Background & aims: Currently there is no FDA-approved therapy for nonalcoholic steatohepatitis (NASH). Increased n-6/n-3 polyunsaturated fatty acids (PUFA) ratio can induce endoplasmic reticulum (ER) stress and mitochondrial dysfunction that characterize NASH. Our recent study with n-3 PUFA showed improvement in individual histologic parameters like steatosis, ballooning and lobular inflammation. We hypothesized that n-3 PUFA therapy mediated improvement in histologic parameters is modulated by lipidomic and proteomic changes. Methods: We therefore evaluated hepatic proteomic and plasma lipidomic profiles before and after n-3 PUFA therapy in subjects with NASH. In a double-blind, randomized, placebo-controlled trial, patients with NASH received 6-month treatment with n-3 PUFA (0.945 g/day [64% alpha-linolenic (ALA), 21% eicosapentaenoic (EPA), and 16% docosahexaenoic (DHA) acids]). Paired liver biopsy and plasma collected before and after-n-3 PUFA therapy were assessed using mass spectrometry and gas chromatography for hepatic proteomics and plasma lipidomics. Data were matched to UniProt and LIPID MAPS database, respectively. Cytoscape software was used to analyze functional pathways. Twenty-seven NASH patients with paired liver histology and plasma before and after n-3 PUFA treatment were studied. Results: Treatment with n-3 PUFA significantly increased ALA, EPA, and glycerophospholipids, and decreased arachidonic acid (p < 0.05 for all). Further, proteomic markers of cell matrix, lipid metabolism, ER stress and cellular respiratory pathways were also modulated. Interestingly, these alterations reflected functional changes highly suggestive of decreased cellular lipotoxicity potential; reduced ER proteasome degradation of proteins and induction of chaperones; and a shift in cell energy homeostasis towards mitochondrial beta-oxidation. Conclusion: Six-month treatment with omega-3 PUFAs significantly improved hepatic proteomic and plasma lipidomic markers of lipogenesis, endoplasmic reticulum stress and mitochondrial functions in patients with NASH.
dc.description.sponsorship · Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [2011/09234-9, 2013/03742-8]
dc.language.iso eng
dc.relation.ispartof Clinical Nutrition
dc.rights restrictedAccess
dc.subject Omega-3 PUFA; NASH; Proteomic; Lipidomic; Mitochondrial dysfunction; Endoplasmic reticulum stress
dc.subject.other nonalcoholic fatty liver; endoplasmic-reticulum stress; binding protein; energy homeostasis; hepatic steatosis; disease; acid; steatohepatitis; cells; gene
dc.title Omega-3 PUFA modulate lipogenesis, ER stress, and mitochondrial dysfunction markers in NASH - Proteomic and lipidomic insight
dc.type article
dc.rights.holder Copyright CHURCHILL LIVINGSTONE LIM/07 LIM/14 LIM/35
dc.identifier.doi 10.1016/j.clnu.2017.08.031
dc.identifier.pmid 29249532
dc.type.category original article
dc.type.version publishedVersion OKADA, Livia Samara dos Reis Rodrigues:FM: OLIVEIRA, Claudia P.:FM:MGT STEFANO, Jose Tadeu:FM: ALVES, Venancio Avancini Ferreira:FM:MPT TORRINHAS, Raquel Susana:FM:MGT CARRILHO, Flair Jose:FM:MGT WAITZBERG, Dan L.:FM:MGT · NOGUEIRA, Monize Aydar:Univ Sao Paulo, Sch Med, Dept Gastroenterol LIM 07 LIM 35, Sao Paulo, Brazil
· SILVA, Ismael Dale Cotrim Guerreiro da:Sao Paulo Fed Univ, Dept Gynecol, Lab Mol Gynecol, Sao Paulo, SP, Brazil
· CORDEIRO, Fernanda Bertucce:Sao Paulo Fed Univ, Dept Surg, Div Urol, Human Reprod Sect, Sao Paulo, Brazil
· PURI, Puneet:Virginia Commonwealth Univ, Richmond, VA USA WOS:000447578700005 2-s2.0-85039435885 EDINBURGH SCOTLAND
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dc.description.index MEDLINE
dc.identifier.eissn 1532-1983
hcfmusp.citation.scopus 9
hcfmusp.citation.wos 6 Brasil Estados Unidos

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