Altered vitamin A metabolism in human liver slices corresponds to fibrogenesis

Abstract

All‐trans‐retinoic acid (atRA), the active metabolite of vitamin A, has antifibrogenic properties in vitro and in animal models. Liver vitamin A homeostasis is maintained by cell‐specific enzymatic activities including storage in hepatic stellate cells (HSCs), secretion into circulation from hepatocytes, and formation and clearance of atRA. During chronic liver injury, HSC activation is associated with a decrease in liver retinyl esters and retinol concentrations. atRA is synthesized through two enzymatic steps from retinol, but it is unknown if the loss of retinoid stores is associated with changes in atRA formation and which cell types contribute to the metabolic changes. The aim of this study was to determine if the vitamin A metabolic flux is perturbed in acute liver injury, and if changes in atRA concentrations are associated with HSC activation and collagen expression. At basal levels, HSC and Kupffer cells expressed key genes involved in vitamin A metabolism, whereas after acute liver injury, complex changes to the metabolic flux were observed in liver slices. These changes include a reproducible spike in atRA tissue concentrations, decreased retinyl ester and atRA formation rate, and time‐dependent changes to the expression of metabolizing enzymes. Kinetic simulations suggested that oxidoreductases are important in determining retinoid metabolic flux after liver injury. These early changes precede HSC activation and upregulation of profibrogenic gene expression, which were inversely correlated with atRA tissue concentrations, suggesting that HSC and Kupffer cells are key cells involved in changes to vitamin A metabolic flux and signaling after liver injury. WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Vitamin A is metabolized in the liver for storage as retinyl esters in hepatic stellate cell (HSCs) or to all‐trans‐retinoic acid (atRA), an active metabolite with antifibrogenic properties. Following chronic liver injury, vitamin A metabolic flux is perturbed, and HSC activation leads to diminished retinoid stores. WHAT QUESTION DID THIS STUDY ADDRESS? Do changes in the expression of vitamin A metabolizing enzymes explain changes in atRA concentrations and the regulation of fibrosis following acute liver injury? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? In healthy liver, both HSC and Kupffer cells may mediate vitamin A homeostasis. Following acute liver injury, complex changes in metabolizing enzyme expression/activity alter the metabolic flux of retinoids, resulting in a transient peak in atRA concentrations. The atRA concentrations are inversely correlated with profibrogenic gene expression, HSC activation, and collagen deposition. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Improved understanding of altered vitamin A metabolic flux in acute liver injury may provide insight into cell‐specific contributions to vitamin A loss and lead to novel interventions in liver fibrosis.

Retinoids in the Pathogenesis and Treatment of Liver Diseases

“…For reasons that remain unclear, data show that hepatic retinoid levels are reduced in high-fat diet (HFD) and genetic murine models of NAFLD [ 71 , 72 , 73 , 74 ], human NAFLD [ 71 , 72 , 75 , 76 ], and acute liver injury [ 77 ]. The liver is the primary organ for retinoid storage, with approximately 80% of the total body retinoid pool stored as retinyl esters in triglyceride-rich lipid droplets in quiescent hepatic stellate cells (HSCs), specialized mesenchymal cells of the liver [ 78 ].…”

Evidence of depot‐specific regulation of all‐trans‐retinoic acid biosynthesis in human adipose tissue

“…Indeed, the primary role of ALDH1A1 is the detoxification of reactive lipid aldehydes in the human lens and mouse liver 30,31 . Our group previously reported that whereas ALDH1A1 expression is high in human hepatocytes, retinoid homeostasis localizes to the stellate cells, 18 again indicating an alternative function for ALDH1A1 in tissues with high exposure to reactive lipids. These data are consistent with a prior mouse study demonstrating that high fat feeding led to increased ALDH1A1 expression but not tissue at RA concentrations in white adipose tissue 25 and provide a potential model to reconcile these seemingly discordant findings.…”

“…Fundamental questions regarding vitamin A metabolism within human adipose tissue remain unanswered, including which enzymes are responsible for at RA biosynthesis. The aldehyde dehydrogenase 1A (ALDH1A) family of enzymes, 16,17 also known as retinaldehyde dehydrogenases (RALDHs), are the predominant enzymes contributing to at RA biosynthesis in many tissues, but their expression varies among tissues, cell types, and with developmental stage 18–20 . In addition, aldehyde oxidase (AOX) may contribute to at RA biosynthesis 21 .…”

“…The aldehyde dehydrogenase 1A (ALDH1A) family of enzymes, 16 , 17 also known as retinaldehyde dehydrogenases (RALDHs), are the predominant enzymes contributing to at RA biosynthesis in many tissues, but their expression varies among tissues, cell types, and with developmental stage. 18 , 19 , 20 In addition, aldehyde oxidase (AOX) may contribute to at RA biosynthesis. 21 At present, the respective, depot‐specific roles of these enzymes in modulating human adipose tissue at RA concentrations and vitamin A homeostasis are unknown.…”

KIAA1363 affects retinyl ester turnover in cultured murine and human hepatic stellate cells

“…3 C, right). Interestingly, in activated HSCs, which are known to lose their vitamin A stores ( 25 , 26 ), Lrat and Kiaa1363 mRNA expression was inversely regulated. Since Lrat expression in liver is known to be vitamin A sensitive ( 27 ), we explored the possibility whether also Kiaa1363 mRNA would be differently expressed in liver of mice when fed different vitamin A feeding regimes.…”