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Bariatric Surgery

Role of ghrelin isoforms in the mitigation of hepatic inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress after bariatric surgery in rats

International Journal of Obesity volume 44, pages 475–487 (2020)Cite this article

Subjects

Abstract

Background/objectives

Bariatric surgery improves nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain elusive. We evaluated the potential role of ghrelin isoforms in the amelioration of hepatic inflammation after sleeve gastrectomy and Roux-en-Y gastric bypass (RYGB).

Subjects/methods

Plasma ghrelin isoforms were measured in male Wistar rats (n = 129) subjected to surgical (sham operation, sleeve gastrectomy, or RYGB) or dietary interventions [fed ad libitum a normal (ND) or a high-fat diet (HFD) or pair-fed diet]. The effect of acylated and desacyl ghrelin on markers of inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in primary rat hepatocytes under palmitate-induced lipotoxic conditions was assessed.

Results

Plasma desacyl ghrelin was decreased after sleeve gastrectomy and RYGB, whereas the acylated/desacyl ghrelin ratio was augmented. Both surgeries diminished obesity-associated hepatic steatosis, CD68+- and apoptotic cells, proinflammatory JNK activation, and Crp, Tnf, and Il6 transcripts. Moreover, a postsurgical amelioration in the mitochondrial DNA content, oxidative phosphorylation (OXPHOS) complexes I and II, and ER stress markers was observed. Specifically, following bariatric surgery GRP78, spliced XBP-1, ATF4, and CHOP levels were reduced, as were phosphorylated eIF2α. Interestingly, acylated and desacyl ghrelin inhibited steatosis and inflammation of palmitate-treated hepatocytes in parallel to an upregulation of OXPHOS complexes II, III, and V, and a downregulation of ER stress transducers IRE1α, PERK, ATF6, their downstream effectors, ATF4 and CHOP, as well as chaperone GRP78.

Conclusions

Our data suggest that the increased relative acylated ghrelin levels after bariatric surgery might contribute to mitigate obesity-associated hepatic inflammation, mitochondrial dysfunction, and ER stress.

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Acknowledgements

We gratefully acknowledge the valuable collaboration of Beatriz Ramírez (Metabolic Research Laboratory, Clínica Universidad de Navarra) for her technical assistance, and all the staff of the breeding house of the University of Navarra.

Funding

This work was supported by Fondo de Investigación Sanitaria-FEDER (FIS PI16/00221 and PI16/01217) from the Instituto de Salud Carlos III. SE was recipient of a predoctoral grant from the Spanish Ministerio de Educación, Cultura y Deporte (FPU15/02599). CIBEROBN is an initiative of the Instituto de Salud Carlos III, Spain.

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Authors and Affiliations

  1. Metabolic Research Laboratory, Clínica Universidad de Navarra, IdiSNA, Pamplona, Spain

    S. Ezquerro, S. Becerril, L. Méndez-Giménez, F. Mocha, V. Catalán, J. Gómez-Ambrosi, G. Frühbeck & A. Rodríguez

  2. CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain

    S. Ezquerro, S. Becerril, L. Méndez-Giménez, R. Moncada, V. Valentí, J. A. Cienfuegos, V. Catalán, J. Gómez-Ambrosi, G. Frühbeck & A. Rodríguez

  3. Department of Surgery, Clínica Universidad de Navarra, IdiSNA, Pamplona, Spain

    C. Tuero, V. Valentí & J. A. Cienfuegos

  4. Department of Anesthesia, Clínica Universidad de Navarra, IdiSNA, Pamplona, Spain

    R. Moncada

  5. Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK

    K. Piper Hanley

  6. Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, IdiSNA, Pamplona, Spain

    G. Frühbeck

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  1. S. Ezquerro
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Ezquerro, S., Becerril, S., Tuero, C. et al. Role of ghrelin isoforms in the mitigation of hepatic inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress after bariatric surgery in rats. Int J Obes 44, 475–487 (2020). https://doi.org/10.1038/s41366-019-0420-2

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