Impaired Hepatic Vitamin A Metabolism in NAFLD Mice Leading to Vitamin A Accumulation in HepatocytesSummary

Ali Saeed; Paulina Bartuzi; Janette Heegsma; Daphne Dekker; Niels Kloosterhuis; Alain de Bruin; Johan W. Jonker; Bart van de Sluis; Klaas Nico Faber

Cellular and Molecular Gastroenterology and Hepatology (Jan 2021)

Impaired Hepatic Vitamin A Metabolism in NAFLD Mice Leading to Vitamin A Accumulation in HepatocytesSummary

Ali Saeed,
Paulina Bartuzi,
Janette Heegsma,
Daphne Dekker,
Niels Kloosterhuis,
Alain de Bruin,
Johan W. Jonker,
Bart van de Sluis,
Klaas Nico Faber

Affiliations

Ali Saeed: Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan; Ali Saeed, PhD, Department Hepatology & Gastroenterology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. fax: +31(0)503619306.
Paulina Bartuzi: Section of Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Janette Heegsma: Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Laboratory Medicine, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Daphne Dekker: Section of Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Niels Kloosterhuis: Section of Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Alain de Bruin: Section of Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
Johan W. Jonker: Section of Molecular Metabolism and Nutrition, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Bart van de Sluis: Section of Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Klaas Nico Faber: Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Laboratory Medicine, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Correspondence Address correspondence to: Klaas Nico Faber, PhD, Department Hepatology & Gastroenterology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. fax: +31(0)503619306.

Journal volume & issue: Vol. 11, no. 1
pp. 309 – 325.e3

Abstract

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Background & Aims: Systemic retinol (vitamin A) homeostasis is controlled by the liver, involving close collaboration between hepatocytes and hepatic stellate cells (HSCs). Genetic variants in retinol metabolism (PNPLA3 and HSD17B13) are associated with non-alcoholic fatty liver disease (NAFLD) and disease progression. Still, little mechanistic details are known about hepatic vitamin A metabolism in NAFLD, which may affect carbohydrate and lipid metabolism, inflammation, oxidative stress and the development of fibrosis and cancer, e.g. all risk factors of NAFLD. Methods: Here, we analyzed vitamin A metabolism in 2 mouse models of NAFLD; mice fed a high-fat, high-cholesterol (HFC) diet and Leptinob mutant (ob/ob) mice. Results: Hepatic retinol and retinol binding protein 4 (RBP4) levels were significantly reduced in both mouse models of NAFLD. In contrast, hepatic retinyl palmitate levels (the vitamin A storage form) were significantly elevated in these mice. Transcriptome analysis revealed a hyperdynamic state of hepatic vitamin A metabolism, with enhanced retinol storage and metabolism (upregulated Lrat, Dgat1, Pnpla3, Raldh’s and RAR/RXR-target genes) in fatty livers, in conjunction with induced hepatic inflammation (upregulated Cd68, Tnfα, Nos2, Il1β, Il-6) and fibrosis (upregulated Col1a1, Acta2, Tgfβ, Timp1). Autofluorescence analyses revealed prominent vitamin A accumulation in hepatocytes rather than HSC in HFC-fed mice. Palmitic acid exposure increased Lrat mRNA levels in primary rat hepatocytes and promoted retinyl palmitate accumulation when co-treated with retinol, which was not detected for similarly-treated primary rat HSCs. Conclusion: NAFLD leads to cell type-specific rearrangements in retinol metabolism leading to vitamin A accumulation in hepatocytes. This may promote disease progression and/or affect therapeutic approaches targeting nuclear receptors.

Published in Cellular and Molecular Gastroenterology and Hepatology

ISSN: 2352-345X (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.journals.elsevier.com/cellular-and-molecular-gastroenterology-and-hepatology/

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