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

Wagner, Carina; Hois, Victoria; Eggeling, Annalena; Pusch, Lisa-Maria; Pajed, Laura; Starlinger, Patrick; Claudel, Thierry; Trauner, Michael; Zimmermann, R.; Taschler, Ulrike; Lass, Achim

doi:10.1016/j.jlr.2022.100173

Cited by 5 publications

(18 citation statements)

References 42 publications

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“…Accordingly, qPCR measurements showed that murine KIAA1363 is expressed in non-parenchymal hepatic stellate cells but not hepatocytes [12]. Since hepatic stellate cells comprise around 5-8% of all liver cells, this may explain why KIAA1363 expression is basically undetectable in whole liver by Northern or Western blotting [9,12]. Interestingly, murine KIAA1363 mRNA expression in hepatic stellate cells was found to be induced (4-fold) upon stellate cell activation [12], a process that occurs in vitro upon cultivation of isolated stellate cells.…”

Section: Tissue Expression Pattern and Regulation Of Expressionmentioning

confidence: 99%

“…Promoter sequences of the human and murine NCEH1/Nceh1 genes that regulate its tissue-specific expression have not been investigated in detail. In any case, several studies have shown that KIAA1363 s mRNA is regulated by certain nuclear receptor [10], coactivators [11], and also by changes in dietary composition [12], demonstrating that KIAA1363 is not constitutively expressed but underlies regulation. Furthermore, the observed nutritional regulation implies that KIAA1363 s mRNA may also, similar to AADAC [3], be diurnally regulated; however, evidence for this is lacking.…”

Section: Tissue Expression Pattern and Regulation Of Expressionmentioning

confidence: 99%

“…It was reasoned that KIAA1363 may be expressed exclusively in certain liver cell types, such as the lipid storing hepatic stellate cells, which may explain the aforementioned lack of KIAA1363 mRNA expression in liver [9,19]. Accordingly, qPCR measurements showed that murine KIAA1363 is expressed in non-parenchymal hepatic stellate cells but not hepatocytes [12]. Since hepatic stellate cells comprise around 5-8% of all liver cells, this may explain why KIAA1363 expression is basically undetectable in whole liver by Northern or Western blotting [9,12].…”

Section: Tissue Expression Pattern and Regulation Of Expressionmentioning

confidence: 99%

“…Since hepatic stellate cells comprise around 5-8% of all liver cells, this may explain why KIAA1363 expression is basically undetectable in whole liver by Northern or Western blotting [9,12]. Interestingly, murine KIAA1363 mRNA expression in hepatic stellate cells was found to be induced (4-fold) upon stellate cell activation [12], a process that occurs in vitro upon cultivation of isolated stellate cells. This suggests that KIAA1363 expression may also be induced upon liver injury in vivo, a process known to activate hepatic stellate cells, which then initiates the trans-differentiation into myofibroblast-like cells and the concomitant loss of their lipid stores, most prominently of vitamin A.…”

Section: Tissue Expression Pattern and Regulation Of Expressionmentioning

confidence: 99%

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KIAA1363—A Multifunctional Enzyme in Xenobiotic Detoxification and Lipid Ester Hydrolysis

et al. 2022

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KIAA1363, annotated as neutral cholesterol ester hydrolase 1 (NCEH1), is a member of the arylacetamide deacetylase (AADAC) protein family. The name-giving enzyme, AADAC, is known to hydrolyze amide and ester bonds of a number of xenobiotic substances, as well as clinical drugs and of endogenous lipid substrates such as diglycerides, respectively. Similarly, KIAA1363, annotated as the first AADAC-like protein, exhibits enzymatic activities for a diverse substrate range including the xenobiotic insecticide chlorpyrifos oxon and endogenous substrates, acetyl monoalkylglycerol ether, cholesterol ester, and retinyl ester. Two independent knockout mouse models have been generated and characterized. However, apart from reduced acetyl monoalkylglycerol ether and cholesterol ester hydrolase activity in specific tissues and cell types, no gross-phenotype has been reported. This raises the question of its physiological role and whether it functions as drug detoxifying enzyme and/or as hydrolase/lipase of endogenous substrates. This review delineates the current knowledge about the structure, function and of the physiological role of KIAA1363, as evident from the phenotypical changes inflicted by pharmacological inhibition or by silencing as well as knockout of KIAA1363 gene expression in cells, as well as mouse models, respectively.

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Section: Tissue Expression Pattern and Regulation Of Expressionmentioning

confidence: 99%

Section: Tissue Expression Pattern and Regulation Of Expressionmentioning

confidence: 99%

Section: Tissue Expression Pattern and Regulation Of Expressionmentioning

confidence: 99%

Section: Tissue Expression Pattern and Regulation Of Expressionmentioning

confidence: 99%

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KIAA1363—A Multifunctional Enzyme in Xenobiotic Detoxification and Lipid Ester Hydrolysis

et al. 2022

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“…Hepatic retinol stores can be mobilized upon increased demand. As needed, retinyl esters of HSCs are hydrolyzed via several hepatic lipases and transferred to hepatocytes [ 147 , 148 , 149 , 150 , 151 , 152 ]. Hepatocytes secrete retinol bound to retinol binding protein (RBP, encoded by RBP4), and associated with transthyretin (TTR) [ 153 , 154 , 155 , 156 , 157 ].…”

Section: Vitamin a Storagementioning

confidence: 99%

Mechanisms of Feedback Regulation of Vitamin A Metabolism

2022

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Vitamin A is an essential nutrient required throughout life. Through its various metabolites, vitamin A sustains fetal development, immunity, vision, and the maintenance, regulation, and repair of adult tissues. Abnormal tissue levels of the vitamin A metabolite, retinoic acid, can result in detrimental effects which can include congenital defects, immune deficiencies, proliferative defects, and toxicity. For this reason, intricate feedback mechanisms have evolved to allow tissues to generate appropriate levels of active retinoid metabolites despite variations in the level and format, or in the absorption and conversion efficiency of dietary vitamin A precursors. Here, we review basic mechanisms that govern vitamin A signaling and metabolism, and we focus on retinoic acid-controlled feedback mechanisms that contribute to vitamin A homeostasis. Several approaches to investigate mechanistic details of the vitamin A homeostatic regulation using genomic, gene editing, and chromatin capture technologies are also discussed.

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Lipid droplets, the Holy Grail of hepatic stellate cells: In health and hepatic fibrosis

Mak

Cheng

2022

The Anatomical Record

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Lipid droplets (LDs) are distinct morphological markers of hepatic stellate cells (HSCs). They are composed of a core of predominantly retinyl esters and triacylglycerols surrounded by a phospholipid layer; the latter harbors perilipins 2, 3, and 5, which help control LD lipolysis. Electron microscopy distinguishes between Types I and II LDs. Type I LDs are surrounded by acid phosphatase-positive lysosomes, which likely digest LDs. LD count and retinoid concentration are modulated by vitamin A intake. Alcohol consumption depletes hepatic retinoids and HSC LDs, with concomitant transformation of HSCs to fibrogenic myofibroblast-like cells. LD loss and accompanying HSC activation occur in HSC cell culture models. Loss of LDs is a consequence of and not a prerequisite for HSC activation. LDs are endowed with enzymes for synthesizing retinyl esters and triacylglycerols as well as neutral lipases and lysosomal acid lipase for breaking down LDs. HSCs have two distinct metabolic LD pools: an "original" pool in quiescent HSCs and a "new" pool emerging in HSC activation; this two-pool model provides a platform for analyzing LD dynamics in HSC activation. Besides lipolysis, LDs are degraded by lipophagy; however, the coordination between and relative contributions of these two pathways to LD removal are unclear. While induction of autophagy accelerates LD loss in quiescent HSCs and promotes HSC activation, blocking autophagy impairs LD degradation and inhibits HSC activation and fibrosis. This article is a critique of five decades of investigations into the morphology, molecular structure, synthesis, and degradation of LDs associated with HSC activation and fibrosis.

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

Cited by 5 publications

References 42 publications

KIAA1363—A Multifunctional Enzyme in Xenobiotic Detoxification and Lipid Ester Hydrolysis

KIAA1363—A Multifunctional Enzyme in Xenobiotic Detoxification and Lipid Ester Hydrolysis

Mechanisms of Feedback Regulation of Vitamin A Metabolism

Lipid droplets, the Holy Grail of hepatic stellate cells: In health and hepatic fibrosis

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