Lívia Samara Dos Reis Rodrigues Okada1, Claudia P Oliveira2, José Tadeu Stefano1, Monize Aydar Nogueira1, Ismael Dale Cotrim Guerreiro da Silva3, Fernanda Bertucce Cordeiro4, Venâncio Avancini Ferreira Alves5, Raquel Susana Torrinhas1, Flair José Carrilho1, Puneet Puri6, Dan L Waitzberg7. 1. Department of Gastroenterology (LIM-07/LIM-35), University of Sao Paulo School of Medicine, Sao Paulo, Brazil. 2. Department of Gastroenterology (LIM-07/LIM-35), University of Sao Paulo School of Medicine, Sao Paulo, Brazil. Electronic address: claudia.oliveira220@fm.usp.br. 3. Laboratory of Molecular Gynecology, Department of Gynecology, Sao Paulo Federal University, São Paulo, SP, Brazil. 4. Human Reproduction Section, Division of Urology, Department of Surgery, Sao Paulo Federal University, São Paulo, Brazil. 5. Department of Pathology (LIM-14), University of Sao Paulo School of Medicine, Sao Paulo, Brazil. 6. Virginia Commonwealth University-VCU, Richmond, VA, USA. 7. Department of Gastroenterology (LIM-07/LIM-35), University of Sao Paulo School of Medicine, Sao Paulo, Brazil. Electronic address: dan@ganep.com.br.
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.
RCT Entities:
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.
Authors: Jessica L Bauer; Katherine Kuhn; Andrew P Bradford; Zain A Al-Safi; Mary A Harris; Robert H Eckel; Celeste Y Robledo; Anahit Malkhasyan; Joshua Johnson; Nancy R Gee; Alex J Polotsky Journal: Reprod Sci Date: 2019-02-17 Impact factor: 3.060
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