Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade

Sandra Rayego‐Mateos; José Luis Morgado‐Pascual; Cristina García‐Caballero; Iolanda Lazaro; Aleix Sala‐Vila; Lucas Opazo‐Rios; Sebastian Mas‐Fontao; Jesús Egido; Marta Ruiz‐Ortega; Juan Antonio Moreno

doi:10.1002/path.6161

journal article Open Access Aug 09, 2023

Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade

Sandra Rayego‐Mateos José Luis Morgado‐Pascual Cristina García‐Caballero Iolanda Lazaro

Aleix Sala‐Vila Lucas Opazo‐Rios Sebastian Mas‐Fontao Jesús Egido Marta Ruiz‐Ortega Juan Antonio Moreno

The Journal of Pathology Vol. 261 No. 2 pp. 169-183 · Wiley

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Abstract

AbstractIntravascular hemolysis is a common feature of different clinical entities, including sickle cell disease and malaria. Chronic hemolytic disorders are associated with hepatic damage; however, it is unknown whether heme disturbs lipid metabolism and promotes liver steatosis, thereby favoring the progression to nonalcoholic fatty liver disease (NAFLD). Using an experimental model of acute intravascular hemolysis, we report here the presence of liver injury in association with microvesicular lipid droplet deposition. Hemolysis promoted serum hyperlipidemia and altered intrahepatic triglyceride fatty acid composition, with increments in oleic, palmitoleic, and palmitic acids. These findings were related to augmented expression of transporters involved in fatty acid uptake (CD36 and MSR1) and deregulation of LDL transport, as demonstrated by decreased levels of LDL receptor and increased PCSK9 expression. Hemolysis also upregulated hepatic enzymes associated with cholesterol biosynthesis (SREBP2, HMGC1, LCAT, SOAT1) and transcription factors regulating lipid metabolism (SREBP1). Increased LC3II/LC3I ratio and p62/SQSTM1 protein levels were reported in mice with intravascular hemolysis and hepatocytes stimulated with heme, indicating a blockade of lipophagy. In cultured hepatocytes, cell pretreatment with the autophagy inductor rapamycin diminished heme‐mediated toxicity and accumulation of lipid droplets. In conclusion, intravascular hemolysis enhances liver damage by exacerbating lipid accumulation and blocking the lipophagy pathway, thereby promoting NAFLD. These new findings have a high translational potential as a novel NAFLD‐promoting mechanism in individuals suffering from severe hemolysis episodes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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Details

Published: Aug 09, 2023
Vol/Issue: 261(2)
Pages: 169-183
License: View

Authors

S

Sandra Rayego‐Mateos

Molecular and Cellular Biology in Renal and Vascular Pathology. IIS‐Fundación Jiménez Díaz Universidad Autónoma Madrid Madrid Spain; Maimonides Biomedical Research Institute of Cordoba (IMIBIC) Hospital Universitario Reina Sofía Cordoba Spain

J

José Luis Morgado‐Pascual

Maimonides Biomedical Research Institute of Cordoba (IMIBIC) Hospital Universitario Reina Sofía Cordoba Spain; Department of Cell Biology, Physiology and Immunology University of Cordoba Cordoba Spain

C

Cristina García‐Caballero

Maimonides Biomedical Research Institute of Cordoba (IMIBIC) Hospital Universitario Reina Sofía Cordoba Spain

I

Iolanda Lazaro

Cardiovascular Risk and Nutrition Hospital del Mar Medical Research Institute (IMIM) Barcelona Spain

A

Aleix Sala‐Vila

Cardiovascular Risk and Nutrition Hospital del Mar Medical Research Institute (IMIM) Barcelona Spain

L

Lucas Opazo‐Rios

Health Science Faculty Universidad de Las Américas Concepción‐Talcahuano Chile

S

Sebastian Mas‐Fontao

Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) Madrid Spain; Biomedical Research Networking Center on Cardiovascular Diseases (CIBERCV) Madrid Spain; Instituto de Investigación Sanitaria (IIS)‐Fundación Jiménez Díaz, Universidad Autónoma Madrid Spain

J

Jesús Egido

Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) Madrid Spain; Instituto de Investigación Sanitaria (IIS)‐Fundación Jiménez Díaz, Universidad Autónoma Madrid Spain

M

Marta Ruiz‐Ortega

Molecular and Cellular Biology in Renal and Vascular Pathology. IIS‐Fundación Jiménez Díaz Universidad Autónoma Madrid Madrid Spain

J

Juan Antonio Moreno

Maimonides Biomedical Research Institute of Cordoba (IMIBIC) Hospital Universitario Reina Sofía Cordoba Spain; Department of Cell Biology, Physiology and Immunology University of Cordoba Cordoba Spain; Biomedical Research Networking Center on Cardiovascular Diseases (CIBERCV) Madrid Spain

Funding

European Social Fund

Instituto de Salud Carlos III Award: PI17/00130

European Regional Development Fund

MINISTERIO DE CIENCIA E INNOVACIÓN Award: FJC2019‐042028‐I

Sociedad Española de Nefrología

Cite This Article

Sandra Rayego‐Mateos, José Luis Morgado‐Pascual, Cristina García‐Caballero, et al. (2023). Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade. The Journal of Pathology, 261(2), 169-183. https://doi.org/10.1002/path.6161

Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade

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