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Molecular and cellular mechanisms underlying the hepatoprotective role of ghrelin against NAFLD progression

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Abstract

The underlying mechanisms for the development and progression of nonalcoholic fatty liver disease (NAFLD) are complex and multifactorial. Within the last years, experimental and clinical evidences support the role of ghrelin in the development of NAFLD. Ghrelin is a gut hormone that plays a major role in the short-term regulation of appetite and long-term regulation of adiposity. The liver constitutes a target for ghrelin, where this gut-derived peptide triggers intracellular pathways regulating lipid metabolism, inflammation, and fibrosis. Interestingly, circulating ghrelin levels are altered in patients with metabolic diseases, such as obesity, type 2 diabetes, and metabolic syndrome, which, in turn, are well-known risk factors for the pathogenesis of NAFLD. This review summarizes the molecular and cellular mechanisms involved in the hepatoprotective action of ghrelin, including the reduction of hepatocyte lipotoxicity via autophagy and fatty acid β-oxidation, mitochondrial dysfunction, endoplasmic reticulum stress and programmed cell death, the reversibility of the proinflammatory phenotype in Kupffer cells, and the inactivation of hepatic stellate cells. Together, the metabolic and inflammatory pathways regulated by ghrelin in the liver support its potential as a therapeutic target to prevent NAFLD in patients with metabolic disorders.

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Funding

This work was supported by Fondo de Investigación Sanitaria-FEDER (PI19/00785 and PI19/00990) from the Spanish Instituto de Salud Carlos III. CIBEROBN is an initiative of the Instituto de Salud Carlos III, Spain.

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Authors and Affiliations

  1. Department of General Surgery, Clínica Universidad de Navarra, School of Medicine, University of Navarra, Pamplona, Spain

    Carlota Tuero

  2. Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008, Pamplona, Irunlarrea 1, Spain

    Sara Becerril, Silvia Ezquerro, Gabriela Neira, Gema Frühbeck & Amaia Rodríguez

  3. CIBER Fisiopatología de La Obesidad Y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain

    Sara Becerril, Gema Frühbeck & Amaia Rodríguez

  4. Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

    Sara Becerril, Gema Frühbeck & Amaia Rodríguez

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

    Gema Frühbeck

Authors
  1. Carlota Tuero
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  2. Sara Becerril
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  3. Silvia Ezquerro
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  4. Gabriela Neira
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  6. Amaia Rodríguez
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The authors declare that all data were generated in-house and that no paper mill was used. Conceptualization and first draft A.R. Writing and editing were performed by all authors. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Amaia Rodríguez.

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Key points

• Ghrelin induces both hepatic lipogenesis and mechanisms against lipotoxicity via the induction of FFA β-oxidation and autophagy.

• Ghrelin inhibits apoptosis, pyroptosis, and autophagic cell death in hepatocytes.

• Ghrelin prevents the activation of hepatic stellate cells and fibrogenesis.

• Ghrelin reduces the proinflammatory phenotype of Kupffer cells.

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Tuero, C., Becerril, S., Ezquerro, S. et al. Molecular and cellular mechanisms underlying the hepatoprotective role of ghrelin against NAFLD progression. J Physiol Biochem 79, 833–849 (2023). https://doi.org/10.1007/s13105-022-00933-1

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