Deiodinase type 3 (DIO3) limits acinar cell proliferation following acute pancreatitis

AbstractAcute pancreatitis (AP), an acute inflammatory process, can be difficult to diagnose. Activating transcription factor 4 (ATF4) has been reported to participate in the pathogenesis of AP. Additionally, histone deacetylases (HDACs) are shown to be closely related to the development of a variety of diseases, including inflammation disease. In our study, we tried to highlight the role of ATF4 in AP through regulation of HDAC1. Firstly, we validated the effect of ATF4 on pancreatic acinar cell proliferation, apoptosis, and inflammation through in vitro experiments on cellular models of caerulein-induced AP. Next, we examined the correlation between ATF4 and HDAC1, and between HDAC1 with neutral endopeptidase (NEP) and kruppel-like factor 4 (KLF4). Finally, the regulatory role of ATF4 in AP was further assessed by determination of pathological conditions, biochemical indicators and inflammation through in vivo experiments on caerulein-induced AP mouse models. After AP induction, highly expressed ATF4 was observed, and silencing ATF4 could promote pancreatic acinar cell proliferation and inhibit apoptosis. ATF4 could bind to the HDAC1 promoter and upregulate its expression in AP. Moreover, HDAC1 could increase KLF4 expression by inhibiting NEP expression. Functionally, silencing ATF4 could suppress AP through regulation of NEP-mediated KLF4 via downregulation of HDAC1. Above all, our study uncovered the promotive role of ATF4 in AP through upregulation of HDAC1.

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Chaiqin Chengqi Decoction decreases pancreatic acinar cell calcium overload in rats with acute pancreatitis

Journal of Chinese Integrative Medicine ◽

10.3736/jcim20081013 ◽

2008 ◽

Vol 6 (10) ◽

pp. 1054-1058 ◽

Cited By ~ 1

Author(s):

P Xue

Keyword(s):

Acute Pancreatitis ◽

Acinar Cell ◽

Pancreatic Acinar Cell ◽

Calcium Overload ◽

Cell Calcium

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TAZ inhibits acinar cell differentiation but promotes immature ductal cell proliferation in adult mouse salivary glands

Genes to Cells ◽

10.1111/gtc.12879 ◽

2021 ◽

Author(s):

Yosuke Miyachi ◽

Miki Nishio ◽

Junji Otani ◽

Shinji Matsumoto ◽

Akira Kikuchi ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Differentiation ◽

Salivary Glands ◽

Acinar Cell ◽

Adult Mouse ◽

Ductal Cell

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Effect of IS-741 on ethionine-induced acute pancreatitis in rats: relation to pancreatic acinar cell regeneration

Journal of Gastroenterology ◽

10.1007/s005350300045 ◽

2003 ◽

Vol 38 (3) ◽

pp. 260-267 ◽

Cited By ~ 4

Author(s):

Tsunao Imamura ◽

Junichi Niikawa ◽

Katsuya Kitamura ◽

Akira Takahashi ◽

Akitoshi Ikegami ◽

...

Keyword(s):

Acute Pancreatitis ◽

Acinar Cell ◽

Pancreatic Acinar Cell ◽

Cell Regeneration

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Stimulation of stellate cells by injured acinar cells: a model of acute pancreatitis induced by alcohol and fat (VLDL)

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90468.2008 ◽

2009 ◽

Vol 297 (6) ◽

pp. G1163-G1171 ◽

Cited By ~ 25

Author(s):

Marco Siech ◽

Zhengfei Zhou ◽

Shaoxia Zhou ◽

Bernd Bair ◽

Andreas Alt ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Pancreatitis ◽

Acinar Cell ◽

Cell Injury ◽

Stellate Cell ◽

Stellate Cells ◽

Pancreatic Acinar Cell ◽

Pancreatic Stellate Cells ◽

Matrix Synthesis ◽

Repair Mechanisms

Mechanisms leading to acute pancreatitis after a fat-enriched meal combined with excess alcohol are incompletely understood. We have studied the effects of alcohol and fat (VLDL) on pancreatic acinar cell (PAC) function, oxidative stress, and repair mechanisms by pancreatic stellate cells (PSC) leading to fibrogenesis. To do so, PAC (rat) were isolated and cultured up to 24 h. Ethanol and/or VLDL were added to PAC. We measured PAC function (amylase, lipase), injury (lactic dehydrogenase), apoptosis (TUNEL, Apo2.7, annexin V binding), oxidative stress, and lipid peroxidation (conjugated dienes, malondialdehyde, chemoluminescence); we also measured PSC proliferation (bromodeoxyuridine incorporation), matrix synthesis (immunofluorescence of collagens and fibronectin, fibronectin immunoassay), and fatty acids in PAC supernatants (gas chromatography). Within 6 h, cultured PAC degraded and hydrolyzed VLDL completely. VLDL alone (50 μg/ml) and in combination with alcohol (0.2, 0.5, and 1% vol/vol) induced PAC injury (LDL, amylase, and lipase release) within 2 h through generation of oxidative stress. Depending on the dose of VLDL and alcohol, apoptosis and/or necrosis were induced. Antioxidants (Trolox, Probucol) reduced the cytotoxic effect of alcohol and VLDL. Supernatants of alcohol/VLDL-treated PAC stimulated stellate cell proliferation and extracellular matrix synthesis. We concluded that, in the presence of lipoproteins, alcohol induces acinar cell injury. Our results provide a biochemical pathway for the clinical observation that a fat-enriched meal combined with excess alcohol consumption can induce acinar cell injury (acute pancreatitis) followed by repair mechanisms (proliferation and increased matrix synthesis in PSC).

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Induction of pancreatic acinar cell proliferation by thyroid hormone

Journal of Endocrinology ◽

10.1677/joe.1.06110 ◽

2005 ◽

Vol 185 (3) ◽

pp. 393-399 ◽

Cited By ~ 30

Author(s):

G M Ledda-Columbano ◽

A Perra ◽

M Pibiri ◽

F Molotzu ◽

A Columbano

Keyword(s):

Cell Proliferation ◽

Thyroid Hormone ◽

Dna Synthesis ◽

Acinar Cell ◽

Acinar Cells ◽

Pancreatic Acinar Cell ◽

Labeling Index ◽

Metabolic Effects ◽

Brdu Incorporation ◽

Pancreatic Cell

Thyroid hormone is known to elicit diverse cellular and metabolic effects in various organs, including mitogenesis in the rat liver. In the present study, experiments were carried out to determine whether thyroid hormone is able to stimulate cell proliferation in another quiescent organ such as the pancreas. 3,5,3′-l-tri-iodothyronine (T3) added to the diet at a concentration of 4 mg/kg caused a striking increase in nuclear bromodeoxyuridine (BrdU) incorporation of rat acinar cells 7 days after treatment (the labeling index was 46.7% in T3-treated rats vs 7.1% in controls). BrdU incorporation was limited to the acinar cells, with duct cells and islet cells being essentially negative. The increase in DNA synthesis was accompanied by the presence of several mitotic figures. Histological examination of the pancreas did not exhibit any sign of T3-induced toxicity. Determination of the apoptotic index, measurement of the serum levels of α-amylase and lipase, and glycemia determination did not show any increase over control values, suggesting that the enhanced proliferation of acinar cells was a direct effect induced by T3 and not a regenerative response consequent to acinar or β-cell injury. Additional experiments showed that DNA synthesis was induced as early as 2 days after T3 treatment (the labeling index was 9.4 vs 1.9% in controls) and was associated with increased protein levels of cyclin D1, cyclin A and proliferating cell nuclear antigen, with no substantial differences in the expression of the cyclin-dependent kinase inhibitor p27. The mitogenic effect of T3 on the pancreas was not limited to the rat, since extensive acinar cell proliferation was also observed in the pancreas of mice treated with T3 for 1 week (the labeling index was 28% in T3-treated mice vs 1.8% in controls). Treatment with three other ligands of nuclear receptors, ciprofibrate, all-trans retinoic acid and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, induced little or no pancreatic cell proliferation. These results demonstrated that T3 is a powerful inducer of cell proliferation in the pancreas and suggested that pancreatic acinar cell proliferation by selected agents may have potential for therapeutic use.

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