Hepatic stellate cell lipid droplets: A specialized lipid droplet for retinoid storage

Blaner, William S.; O’Byrne, Sheila M.; Wongsiriroj, Nuttaporn; Kluwe, Johannes; D'Ambrosio, Diana M.; Jiang, Hongfeng; Schwabe, Robert F.; Hillman, Elizabeth M. C.; Piantedosi, Roseann; Libien, Jenny

doi:10.1016/j.bbalip.2008.11.001

Cited by 360 publications

(388 citation statements)

References 64 publications

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“…11 Lecithin-retinol acyltransferase acts as the sole retinol acyltransferase in the liver and is responsible for the formation of retinyl esters in HSC. 1 Lecithin-retinol acyltransferase is highly expressed in HSC and downregulated during HSC activation. 46 Lrat − / − mice showed a striking total absence of large lipid-containing droplets that normally store hepatic retinoid within HSC.…”

Section: Discussionmentioning

confidence: 99%

“…These two classes of lipids account for approximately three-quarters of the total lipids in LDs of HSC. 1 Accumulating evidence has shown the importance of cellular lipids in maintaining HSC in quiescent state. 12,13 Restoration of lipogenesis and elevation of cellular lipid content in HSC might be a strategy for attenuating HSC activation and inhibiting fibrogenesis.…”

mentioning

confidence: 99%

“…Perilipins are crucial for the formation of cellular LDs and modulation of lipid homeostasis by regulating the storage and utilization of intracellular lipids. 1 Perilipins are numbered in the order of discovery. 2 Plin1 (Perilipin) and Plin2 (Adipophilin) are exclusively associated with LDs and are degraded when not bound to LDs.…”

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confidence: 99%

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Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Lin

Chen

2016

Laboratory Investigation

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Hepatic stellate cells (HSC) are major effectors during hepatic fibrogenesis. The activation of HSC is coupled to the loss of lipid droplets (LDs), which are specialized organelles composed of neutral lipids surrounded by perilipins. LDs have emerged as a focal point of interest in understanding the metabolic regulation of intrahepatic lipids during lipid-mediated liver fibrogenesis. Perilipin 5 (Plin5) is a newly identified LD protein in the perilipin family, which plays a key role in regulating aspects of intracellular trafficking, signaling, and cytoskeletal organization in hepatocytes. Recent work in Plin5 knockout mice suggests a role in high fat diet-induced hepatic lipotoxicity. The current report is to evaluate the impact of Plin5 on HSC activation and to elucidate the underlying mechanisms. We now show that high fat diet-induced liver fibrosis is accompanied by an approximate 75% reduction in Plin5 in HSC, and that spontaneous activation of primary HSC produces temporally coincident loss of Plin5 expression and LD depletion. As modulating lipid content in HSC is a suggested strategy for inhibition of HSC activation and treatment of hepatic fibrosis, we asked whether exogenous Plin5 expression in primary HSC would reverse the activation phenotype and promote LD formation. Recombinant lentiviral Plin5 expression in primary mouse HSC restored the formation of LDs, increased lipid content by inducing expression of pro-lipogenic genes and suppressing expression of pro-lipolytic genes, and suppressed HSC activation (~two fold reduction in expression of procollagen and α-smooth muscle actin, two unique biomarkers for activated HSC). In addition, the expression of exogenous Plin5 in HSC attenuated cellular oxidative stress by reducing cellular reactive oxygen species, elevating cellular glutathione, and inducing gene expression of glutamate-cysteine ligase. Taken together, our results indicate that expression of Plin5 plays a critical role in the formation of LDs, the elevation of lipid content in HSC, and the inhibition of the activation of HSC.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Lin

Chen

2016

Laboratory Investigation

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“…The major part of retinoids is concentrated in the lipid droplets of hepatic stellate cells Moriwaki et al, 1988;Blomhoff et al, 1991;Blaner et al, 2009), where nearly all of the retinoids present is stored as retinyl ester (primarily retinyl palmitate, with smaller amounts of retinyl stearate, retinyl oleate and retinyl linoleate) (Blaner et al, 1985;Blomhoff et al, 1991;Blaner et al, 2009). Unesterified retinol accounts for less than 1 %.…”

Section: Liver Storesmentioning

confidence: 99%

Scientific Opinion on Dietary Reference Values for vitamin A

Products¹

2015

EFSA Journal

130

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Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies derived Dietary Reference Values for vitamin A. The Panel considered that a concentration of 20 µg retinol/g liver can be used as a target for establishing the Average Requirement (AR) for vitamin A. In the absence of a better characterisation of the relationship between vitamin A intake and liver stores, a factorial approach was applied. This approach considered a total body/liver retinol store ratio of 1.25, a liver/body weight ratio of 2.4 %, a fractional catabolic rate of body retinol of 0.7 % per day, an efficiency of storage in the whole body for ingested retinol of 50 % and reference weights for women and men in the EU of 58.5 and 68.1 kg, respectively. ARs of 570 µg retinol equivalent (RE)/day for men and 490 µg RE/day for women were derived. Assuming a coefficient of variation (CV) of 15 %, Population Reference Intakes (PRIs) of 750 µg RE/day for men and 650 µg RE/day for women were set. For infants aged 7-11 months and children, the same equation as for adults was applied by using specific values for reference weight and liver/body weight ratio. For catabolic rate, the adult value corrected on the basis of a growth factor was used. ARs range from 190 µg RE/day in infants aged 7-11 months to 580 µg RE/day in boys aged 15-17 years. PRIs for infants and children were estimated using a CV of 15 % and range from 250 to 750 µg RE/day. For pregnancy and lactation, additional vitamin A requirements related to the accumulation of retinol in fetal and maternal tissues and transfer of retinol into breast milk were considered and PRIs of 700 and 1 300 µg RE/day, respectively, were set. Vitamin A is involved in vision as retinal, which plays a central role in the mechanisms of phototransduction, and in the systemic maintenance of the growth and integrity of cells in body tissues through the action of retinoic acid, which acts as regulator of genomic expression. The most specific clinical consequence of vitamin A deficiency is xerophthalmia, which encompasses a clinical spectrum of ocular manifestations. In low-income countries, vitamin A deficiency in young infants and children has been associated with increased infectious morbidity and mortality, including respiratory infection and diarrhoea. © EuropeanPreformed vitamin A is efficiently absorbed (70-90 %). The absorption of β-carotene appears to be highly variable (5-65 %), depending on food-and diet-related factors, genetic characteristics and the health status of the subject. The intestine is the primary tissue where dietary provitamin A carotenoids are converted to retinol. Retinol, in the form of retinyl esters, and provitamin A carotenoids enter the body as a component of nascent chylomicrons secreted into the lymphatic system. Most dietary retinol (in chylomicrons and chylomicron remnants) is taken up by the liver, which is the major site of retinol metabolism and storage. Hepatic retinyl esters are hydrolysed to free retinol, and delivered to ti...

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“…However, PPAR-γ can increase the expression of inhibitory Smad7 (22)(23)(24). PPAR-γ can also restore the ability of HSCs to accumulate retinyl palmitate, a feature of quiescent HSCs (25)(26)(27). Together with a decrease in α-SMA expression, re-expression of PPAR-γ is thought to be an indicator of attenuated HSC activation and even transition to the quiescent state.…”

Section: Introductionmentioning

confidence: 99%

Prolyl oligopeptidase attenuates hepatic stellate cell activation through induction of Smad7 and PPAR-γ

Zhou

Wang

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Prolyl oligopeptidase (POP) is a serine endopeptidase widely distributed in vivo with high activity in the liver. However, its biological functions in the liver have remained largely elusive. A previous study by our group has shown that POP produced N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) and thereby exerted an anti-fibrogenic effect on hepatic stellate cells (HSCs) in vitro. It was therefore hypothesized that POP may affect the activation state of HSCs and has an important role in liver fibrosis. The HSC-T6 immortalized rat liver stellate cell line was treated with the POP inhibitor S17092 or transfected with recombinant lentivirus to overexpress POP. Cell proliferation and apoptosis were determined using a Cell Counting Kit-8 and flow cytometry, respectively. The activation status of HSCs was determined by examination of the expression of α-smooth muscle actin (α-SMA), collagen I, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor (TGF)-β-Smad signaling and peroxisome proliferator activated receptor-γ (PPAR-γ). Inhibition by S17092 decreased, whereas lentiviral expression increased the activity of POP and cell proliferation, while neither of the treatments affected cell apoptosis. Of note, S17092 significantly increased, whereas POP overexpression decreased the expression of α-SMA and MCP-1 without affecting the expression of collagen I and TGF-β1. Furthermore, S17092 caused a reduction, whereas POP overexpression caused an upregulation of Smad7 protein and PPAR-γ, but not phosphorylated-Smad2/3 expression. In conclusion, POP attenuated the activation of HSCs through inhibition of TGF-β signaling and induction of PPAR-γ, which may have therapeutic potential in liver fibrosis.

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Hepatic stellate cell lipid droplets: A specialized lipid droplet for retinoid storage

Cited by 360 publications

References 64 publications

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Scientific Opinion on Dietary Reference Values for vitamin A

Prolyl oligopeptidase attenuates hepatic stellate cell activation through induction of Smad7 and PPAR-γ

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