Retinoids in health and disease: A role for hepatic stellate cells in affecting retinoid levels

Haaker, Maya W; Vaandrager, Arie B.; Helms, J. Bernd

doi:10.1016/j.bbalip.2020.158674

Cited by 52 publications

(58 citation statements)

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“…Dietary uptake is the exclusive source of vitamin A (VitA) in humans [ 2 ]. Notably, 60–95% of VitA is stored in the liver of healthy individuals, while only minor fractions are located in extrahepatic tissues [ 3 ]. Importantly, activated hepatic stellate cells (HSCs) are the main driver of fibrogenesis upon liver injury by producing extracellular matrix proteins.…”

Section: Introductionmentioning

confidence: 99%

Vitamin A levels reflect disease severity and portal hypertension in patients with cirrhosis

et al. 2020

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Background and Aims The liver plays a key role in the storage, metabolism and homeostasis of fat-soluble vitamins. We investigated the relation of Vitamin(Vit)A/D/E serum levels with severity of liver disease and portal hypertension (PHT). Methods VitA/D/E serum levels were assessed in 234 patients with advanced chronic liver disease (ACLD, i.e. hepatic venous pressure gradient [HVPG] ≥ 6 mmHg). Patients with hepatocellular carcinoma, pre-/post-hepatic PHT, TIPS or liver transplantation were excluded. Results Most patients were male (n = 153; 65%) with a median age of 57.6 (49.7–64.5) years. Thirty-two (14%) patients had HVPG 6–9 mmHg, 66 (28%) 10-15 mmHg, and 136 (58%) ≥ 16 mmHg, respectively. VitD deficiency (25-OH-vitamin-D <50 nmol/L) was found in 133 (57%) with higher prevalence in Child-Turcotte-Pugh (CTP)-C: 85% vs. B: 66% vs. A: 47% (p < 0.001). VitD levels displayed significant but weak correlations with hepatic dysfunction and PHT. VitE levels were normal in 227 (97%) patients and displayed no relevant association with hepatic dysfunction or PHT. Only 63 (27%) patients had normal (>1.05 µmol/L) VitA levels, while 58 (25%) had mild (0.70–1.04 µmol/L), 71 (30%) moderate (0.35–0.69 µmol/L), and 42(18%) severe(<0.35 µmol/L) VitA deficiency. VitA correlated with HVPG (Rho = −0.409), CTP score (Rho = −0.646), and serum bile acid levels (Rho = −0.531; all p < 0.001). The prevalence of decompensated ACLD (dACLD) continuously increased with severity of VitA deficiency (no: 40% vs. mild: 51% vs. moderate: 67% vs. severe: 91% had dACLD; p < 0.001). CTP score (per point; OR 2.46; 95%CI 1.80–3.37; p <0.001), age (per year; OR 0.95; 95%CI 0.92–0.98; p = 0.001) and elevated bile acid levels(>10 µmol/L; OR 3.62; 95%CI 1.61–8.14; p = 0.002) were independently associated with VitA deficiency. Conclusion VitA and VitD but not VitE deficiencies are highly prevalent in ACLD. VitA deficiency strongly correlates with hepatic dysfunction, PHT and bile acid levels and is associated with decompensated ACLD. Trial registration number NCT03267615.

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Section: Introductionmentioning

confidence: 99%

Vitamin A levels reflect disease severity and portal hypertension in patients with cirrhosis

et al. 2020

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“…13 Under normal physiological conditions, HSCs exhibit a quiescent phenotype (qHSC) with lipid-rich granules and are responsible for vitamin A storage and diverse roles like regulation of epithelial cell fate, immune modulation, tissue health, and matrix degradation, etc. 14,15 In the injured liver, qHSCs undergo sequential morphological and physiological changes to maintain the pathophysiological status of the injured liver. 16 (Figure 1).…”

Section: Hepatic Stellate Cellsmentioning

confidence: 99%

Endothelin-1 in portal hypertension: The intricate role of hepatic stellate cells

Ezhilarasan

2020

Exp Biol Med (Maywood)

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Portal hypertension is one of the most important cirrhosis-associated complications of chronic liver disease, leading to significant morbidity and mortality. After chronic liver injury, hepatic stellate cells reside in the perisinusoidal space activted and acquire a myofibroblast-like phenotype. The activated hepatic stellate cells act as both sources as well as the target for a potent vasoconstrictor endothelin-1. Activation of hepatic stellate cells plays a vital role in the onset of cirrhosis by way of increased extracellular matrix production and the enhanced contractile response to vasoactive mediators such as endothelin-1. In fibrotic/cirrhotic liver, activated hepatic stellate cells produce endothelin-1 leading to an imbalance between pro and antifibrotic factors responsible for enormous extracellular matrix synthesis. Thus, extracellular matrix deposition in the perisinusoidal space further augments liver stiffness and elevates the vascular tone and portal hypertension. Portal hypertension is a complex process modulated by several cell types like hepatic stellate cells, liver sinusoidal endothelial cells, Kupffer cells, injured hepatocytes, immune cells, and biliary epithelial cells. Therefore, targeting a single cell type may not be useful for regression of cirrhosis and portal hypertension. Nevertheless, numerous findings indicate that functionally liver sinusoidal endothelial cells and hepatic stellate cells closely regulate the sinusoidal blood flow via synthesis of several vasoactive molecules including endothelin-1, and hence targeting these cells with novel pharmacological agents may offer promising results. Impact statement Portal hypertension is pathologically defined as increase of portal venous pressure, mainly due to chronic liver diseases such as fibrosis and cirrhosis. In fibrotic liver, activated hepatic stellate cells increase their contraction in response to endothelin-1 (ET-1) via autocrine and paracrine stimulation from liver sinusoidal endothelial cells and injured hepatocytes. Clinical studies are limited with ET receptor antagonists in cirrhotic patients with portal hypertension. Hence, studies are needed to find molecules that block ET-1 synthesis. Accumulation of extracellular matrix proteins in the perisinusoidal space, tissue contraction, and alteration in blood flow are prominent during portal hypertension. Therefore, novel matrix modulators should be tested experimentally as well as in clinical studies. Specifically, tumor necrosis factor-α, transforming growth factor-β1, Wnt, Notch, rho-associated protein kinase 1 signaling antagonists, and peroxisome proliferator-activated receptor α and γ, interferon-γ and sirtuin 1 agonists should be tested elaborately against cirrhosis patients with portal hypertension.

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“…After passing through the hepatocytes, dietary retinol is mostly taken up and stored as retinyl-palmitate esters (RE) in lipid droplets characteristic of quiescent HSCs. 10 In response to liver injury HSCs become activated and rapidly loss their vitamin A contents in a process that has been mechanistically linked to CLD progression and the onset of vitamin A deficiency (VAD). 10 On the other hand, on conversion into retinoic acids (RA) vitamin A exerts potent systemic regulatory effects on many physiological processes including lipid and carbohydrate metabolism.…”

mentioning

confidence: 99%

“… 10 In response to liver injury HSCs become activated and rapidly loss their vitamin A contents in a process that has been mechanistically linked to CLD progression and the onset of vitamin A deficiency (VAD). 10 On the other hand, on conversion into retinoic acids (RA) vitamin A exerts potent systemic regulatory effects on many physiological processes including lipid and carbohydrate metabolism. This is achieved through RA binding to retinoid X receptor (RXR) and retinoid acid receptor (RAR) transcription factors, which operate in direct or indirect coordination with the metabolic transcription factors previously mentioned.…”

mentioning

confidence: 99%

“…This is achieved through RA binding to retinoid X receptor (RXR) and retinoid acid receptor (RAR) transcription factors, which operate in direct or indirect coordination with the metabolic transcription factors previously mentioned. 8 , 9 Experimental and clinical findings indicate that normal RA signaling is important to prevent NAFLD, 10 and that patients carrying the NAFLD risk variant of patatin-like phospholipase domain-containing protein 3 ( PNPLA3-I148M ) have low serum retinol concentrations. 11 Moreover, low serum and hepatic retinol levels, taken as indicators of VAD, have been observed in NAFLD patients in association with disease progression.…”

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confidence: 99%

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Vitamin A in Nonalcoholic Fatty Liver Disease: A Key Player in an Offside Position?

Berasain

Avila

2021

Cellular and Molecular Gastroenterology and Hepatology

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Retinoids in health and disease: A role for hepatic stellate cells in affecting retinoid levels

Cited by 52 publications

References 160 publications

Vitamin A levels reflect disease severity and portal hypertension in patients with cirrhosis

Vitamin A levels reflect disease severity and portal hypertension in patients with cirrhosis

Endothelin-1 in portal hypertension: The intricate role of hepatic stellate cells

Vitamin A in Nonalcoholic Fatty Liver Disease: A Key Player in an Offside Position?

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