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Omega-3 PUFA modulate lipogenesis, ER stress, and mitochondrial dysfunction markers in NASH - Proteomic and lipidomic insight.
Clin Nutr 2018; 37(5):1474-1484CN

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.

Authors+Show Affiliations

Department of Gastroenterology (LIM-07/LIM-35), University of Sao Paulo School of Medicine, Sao Paulo, Brazil.Department of Gastroenterology (LIM-07/LIM-35), University of Sao Paulo School of Medicine, Sao Paulo, Brazil. Electronic address: claudia.oliveira220@fm.usp.br.Department of Gastroenterology (LIM-07/LIM-35), University of Sao Paulo School of Medicine, Sao Paulo, Brazil.Department of Gastroenterology (LIM-07/LIM-35), University of Sao Paulo School of Medicine, Sao Paulo, Brazil.Laboratory of Molecular Gynecology, Department of Gynecology, Sao Paulo Federal University, São Paulo, SP, Brazil.Human Reproduction Section, Division of Urology, Department of Surgery, Sao Paulo Federal University, São Paulo, Brazil.Department of Pathology (LIM-14), University of Sao Paulo School of Medicine, Sao Paulo, Brazil.Department of Gastroenterology (LIM-07/LIM-35), University of Sao Paulo School of Medicine, Sao Paulo, Brazil.Department of Gastroenterology (LIM-07/LIM-35), University of Sao Paulo School of Medicine, Sao Paulo, Brazil.Virginia Commonwealth University-VCU, Richmond, VA, USA.Department of Gastroenterology (LIM-07/LIM-35), University of Sao Paulo School of Medicine, Sao Paulo, Brazil. Electronic address: dan@ganep.com.br.

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29249532

Citation

Okada, Lívia Samara Dos Reis Rodrigues, et al. "Omega-3 PUFA Modulate Lipogenesis, ER Stress, and Mitochondrial Dysfunction Markers in NASH - Proteomic and Lipidomic Insight." Clinical Nutrition (Edinburgh, Scotland), vol. 37, no. 5, 2018, pp. 1474-1484.
Okada LSDRR, Oliveira CP, Stefano JT, et al. Omega-3 PUFA modulate lipogenesis, ER stress, and mitochondrial dysfunction markers in NASH - Proteomic and lipidomic insight. Clin Nutr. 2018;37(5):1474-1484.
Okada, L. S. D. R. R., Oliveira, C. P., Stefano, J. T., Nogueira, M. A., Silva, I. D. C. G. D., Cordeiro, F. B., ... Waitzberg, D. L. (2018). Omega-3 PUFA modulate lipogenesis, ER stress, and mitochondrial dysfunction markers in NASH - Proteomic and lipidomic insight. Clinical Nutrition (Edinburgh, Scotland), 37(5), pp. 1474-1484. doi:10.1016/j.clnu.2017.08.031.
Okada LSDRR, et al. Omega-3 PUFA Modulate Lipogenesis, ER Stress, and Mitochondrial Dysfunction Markers in NASH - Proteomic and Lipidomic Insight. Clin Nutr. 2018;37(5):1474-1484. PubMed PMID: 29249532.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Omega-3 PUFA modulate lipogenesis, ER stress, and mitochondrial dysfunction markers in NASH - Proteomic and lipidomic insight. AU - Okada,Lívia Samara Dos Reis Rodrigues, AU - Oliveira,Claudia P, AU - Stefano,José Tadeu, AU - Nogueira,Monize Aydar, AU - Silva,Ismael Dale Cotrim Guerreiro da, AU - Cordeiro,Fernanda Bertucce, AU - Alves,Venâncio Avancini Ferreira, AU - Torrinhas,Raquel Susana, AU - Carrilho,Flair José, AU - Puri,Puneet, AU - Waitzberg,Dan L, Y1 - 2017/09/07/ PY - 2017/07/18/received PY - 2017/08/28/revised PY - 2017/08/30/accepted PY - 2017/12/19/pubmed PY - 2019/11/23/medline PY - 2017/12/19/entrez KW - Endoplasmic reticulum stress KW - Lipidomic KW - Mitochondrial dysfunction KW - NASH KW - Omega-3 PUFA KW - Proteomic SP - 1474 EP - 1484 JF - Clinical nutrition (Edinburgh, Scotland) JO - Clin Nutr VL - 37 IS - 5 N2 - 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. SN - 1532-1983 UR - https://www.unboundmedicine.com/medline/citation/29249532/Omega_3_PUFA_modulate_lipogenesis_ER_stress_and_mitochondrial_dysfunction_markers_in_NASH___Proteomic_and_lipidomic_insight_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0261-5614(17)30314-X DB - PRIME DP - Unbound Medicine ER -