Uroguanylin prevents hepatic steatosis, mitochondrial dysfunction and fibrosis in obesity-associated NAFLD

Eva M Fernández-Sáez; Maite Losarcos; Sara Becerril; Víctor Valentí; Rafael Moncada; Marina Martín; María A Burrell; Victoria Catalán; Javier Gómez-Ambrosi; Carmen Mugueta; Inmaculada Colina; Camilo Silva; Javier Escalada; Gema Frühbeck; Amaia Rodríguez

doi:10.1016/j.metabol.2023.155663

Uroguanylin prevents hepatic steatosis, mitochondrial dysfunction and fibrosis in obesity-associated NAFLD

Metabolism. 2023 Oct:147:155663. doi: 10.1016/j.metabol.2023.155663. Epub 2023 Jul 29.

Authors

Affiliations

¹ Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.
² Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
³ CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain.
⁴ CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Department of Anesthesia, Clínica Universidad de Navarra, Pamplona, Spain.
⁵ Department of Pathology, Anatomy and Physiology, University of Navarra, Pamplona, Spain.
⁶ CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Department of Pathology, Anatomy and Physiology, University of Navarra, Pamplona, Spain.
⁷ Department of Biochemistry, Clínica Universidad de Navarra, Pamplona, Spain.
⁸ Department of Internal Medicine, Clínica Universidad de Navarra, Pamplona, Spain.
⁹ CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Pamplona, Spain.
¹⁰ Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Pamplona, Spain.
¹¹ Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain. Electronic address: [email protected].

PMID: 37517791
DOI: 10.1016/j.metabol.2023.155663

Abstract

Background: The biological mediators supporting the resolution of liver steatosis, inflammation and fibrosis after bariatric surgery in patients with obesity and NAFLD remain unclear. We sought to analyze whether uroguanylin and guanylin, two gut hormones involved in the regulation of satiety, food preference and adiposity, are involved in the amelioration of obesity-associated NAFLD after bariatric surgery.

Methods: Proguanylin (GUCA2A) and prouroguanylin (GUCA2B) were measured in 214 participants undergoing bariatric surgery with biopsy-proven NAFLD diagnosis. Pathways involved in lipid metabolism, mitochondrial network and fibrogenesis were evaluated in liver biopsies (n = 137). The effect of guanylin and uroguanylin on these metabolic functions was assessed in HepG2 hepatocytes and LX-2 hepatic stellate cells (HSC) under lipotoxic and profibrogenic conditions.

Results: Plasma and hepatic expression of GUCA2B were decreased in obesity-associated NAFLD. Both GUCA2A and GUCA2B levels were increased after sleeve gastrectomy and Roux-en-Y gastric bypass in parallel to the improved liver function. The liver of patients with type 2 diabetes showed impaired mitochondrial β-oxidation, biogenesis, dynamics as well as increased fibrosis. Uroguanylin diminished the lipotoxicity in palmitate-treated HepG2 hepatocytes, evidenced by decresased steatosis and lipogenic factors, as well as increased mitochondrial network expression, AMPK-induced β-oxidation and oxygen consumption rate. Additionally, uroguanylin, but not guanylin, reversed HSC myofibroblast transdifferentiation as well as fibrogenesis after TGF-β1 stimulation.

Conclusions: Uroguanylin constitutes a protective factor against lipotoxicity, mitochondrial dysfunction and fibrosis. Increased GUCA2B levels might contribute to improve liver injury in patients with obesity-associated NAFLD after bariatric surgery.

Keywords: Bariatric surgery; Liver fibrosis; Mitochondrial dysfunction; Nonalcoholic fatty liver disease; Uroguanylin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bariatric Surgery*
Diabetes Mellitus, Type 2* / metabolism
Fibrosis
Humans
Liver / metabolism
Mitochondria / metabolism
Non-alcoholic Fatty Liver Disease* / pathology
Obesity / complications
Obesity / metabolism
Obesity / surgery
Obesity, Morbid* / surgery

Substances

uroguanylin