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Impaired hepatic vitamin A metabolism in NAFLD mice leading to vitamin A accumulation in hepatocytes

Saeed, A., Bartuzi, P., Heegsma, J., Dekker, D., Kloosterhuis, N., de Bruin, A., Jonker, J. W., van de Sluis, B. & Faber, K. N., 19-Jul-2020, In : Cellular and molecular gastroenterology and hepatology.

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DOI

BACKGROUND & AIMS: Systemic retinol (vitamin A) homeostasis is controlled by the liver, involving close collaboration between hepatocytes and hepatic stellate cells (HSC). 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 HSC.

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.

Original languageEnglish
JournalCellular and molecular gastroenterology and hepatology
Publication statusE-pub ahead of print - 19-Jul-2020

ID: 130037633