Altered carbohydrate, lipid, and xenobiotic metabolism by liver from rats flown on Cosmos 1887

Merrill, Alfred H.; Hoel, Martha; Wang, Elaine; Mullins, Richard E.; Hargrove, James L.; Jones, Dean P.; Popova, I A

doi:10.1096/fasebj.4.1.2295381

Cited by 44 publications

(30 citation statements)

References 19 publications

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“…3, 4, 5, 6, 50, 51 Previous reports have shown that microgravity induces hepatic injury and apoptosis. 8, 9 It is well known that hepatocyte proliferation is associated with various types of injuries; however, less is known regarding the connection between liver function injury and hepatocyte cell cycle control under microgravity.…”

Section: Discussionmentioning

confidence: 99%

“…Carbohydrates, lipids and enzymes have been reported to be changed under microgravity. 3, 4, 5, 6 Several studies have demonstrated that glycogen, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) of the liver were significantly impacted by spaceflight in humans and rats and by tail suspension (TS) in rats, 7, 8, 9 which suggested that microgravity would lead to liver function derangement. In addition to these alterations of biochemical indexes, simulated microgravity (SMG) induced mild portal endotoxemia, which may contribute to hepatic injury and trigger hepatic apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Upregulation of miR-223 in the rat liver inhibits proliferation of hepatocytes under simulated microgravity

Chen

Yang

et al. 2017

Exp Mol Med

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Long-term spaceflight affects numerous organ systems in the body, including metabolic dysfunction. Recently, ample evidence has demonstrated that the liver is a vulnerable organ during spaceflight. However, the changes in hepatocyte proliferation and cell cycle control under microgravity remain largely unexplored. In the present study, we first confirmed that the serum levels of aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase, biochemical markers of liver function, were altered in rats under tail suspension (TS) conditions to simulate microgravity, as shown in previous reports. Next, we demonstrated that the cell proliferation activity, determined by Ki67, PCNA and PH3, was significantly decreased at the different TS time points (TS for 14, 28 and 42 days) compared with that in the control group. Consistently, the positive cell cycle regulators Ccna2, Ccnd1, Cdk1, Cdk2 and cyclin D3 were also significantly decreased in the TS groups as shown by quantitative real-time PCR and western blotting analysis. Subsequent analysis revealed that the aberrant hepatocyte proliferation inhibition under simulated microgravity was associated with the upregulation of miR-223 in the liver. We further found that miR-223 inhibited the proliferation of Hepa1-6 cells and identified CDK2 and CUL1 as its direct targets. In addition, the decreased expression of CDK2 and CUL1 was negatively correlated with the level of p27 in vitro and in vivo, which may have been responsible for retarding hepatocyte proliferation. Collectively, these data indicate that upregulation of miR-223 was associated with the inhibition of liver cell growth and reveal the role of miR-223 in rat hepatocyte proliferation disorders and the pathophysiological process under simulated microgravity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Upregulation of miR-223 in the rat liver inhibits proliferation of hepatocytes under simulated microgravity

Chen

Yang

et al. 2017

Exp Mol Med

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“…Abraham et al 128 also studied the activities of 28 different hepatic enzymes in microgravity and observed both increases and decreases in some of these enzymes. The activity of hydroxymethylglutaryl‐CoA (HMG‐CoA) reductase, the rate‐limiting step in the biosynthesis of cholesterol, was also shown to increase in microgravity 129 . In rats flown on Cosmos , the amount of microsomal P‐450 and the activity of aniline hydroxylase and ethylmorphine‐N‐demethylase, cytochrome P‐450‐dependent enzymes, were decreased 129 .…”

Section: Physiological Changes During Space Flightmentioning

confidence: 99%

Physiological, Pharmacokinetic, and Pharmacodynamic Changes in Space

Graebe

Schuck

Lensing

et al. 2004

The Journal of Clinical Pharma

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Medications have been taken since the first Mercury flight in 1967 and, since then, have been used for several indications such as space motion sickness, sleeplessness, headache, nausea, vomiting, back pain, and congestion. As the duration of space missions get longer, it is even more likely that astronauts will encounter some of the acute illnesses that are frequently seen on Earth. Microgravity environment induces several physiological changes in the human body. These changes include cardiovascular degeneration, bone decalcification, decreased plasma volume, blood flow, lymphocyte and eosinophil levels, altered hormonal and electrolyte levels, muscle atrophy, decreased blood cell mass, increased immunoglobulin A and M levels, and a decrease in the amount of microsomal P-450 and the activity of some of its dependent enzymes. These changes may be expected to have severe implications on the pharmacokinetic and pharmacodynamic properties of drug substances.

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“…In a study of newts in space, some liver pathology was found in the flight newts, although whether this was directly related to weightlessness was not clear (Yamashita et al 2001). Total cytochrome P450 content and activity were reduced in the livers of rats following 14 d of space flight (Merrill et al 1987;Merrill et al 1990; Rabot et al 2000), and other studies in rats have shown perturbations in liver carbohydrate and lipid metabolism. For example, increased liver triglyceride content (Ahlers et al 1981), changes in fatty acid constitution (Abraham et al 1981), and lower liver cholesterol content (Merrill et al 1987) were found.…”

Section: Introductionmentioning

confidence: 98%

The effects of space flight and microgravity on the growth and differentiation of PICM-19 pig liver stem cells

Talbot

Caperna

Blomberg

et al. 2010

In Vitro Cell.Dev.Biol.-Animal

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The PICM-19 pig liver stem cell line was cultured in space for nearly 16 d on the STS-126 mission to assess the effects of spaceflight on the liver's parenchymal cells-PICM-19 cells to differentiate into either monolayers of fetal hepatocytes or 3-dimensional bile ductules (cholangiocytes). Semi-quantitative data included light microscopic assessments of final cell density, cell morphology, and response to glucagon stimulation and electron microscopic assessment of the cells' ultrastructural features and cell-to-cell connections and physical relationships. Quantitative assessments included assays of hepatocyte detoxification functions, i.e., inducible P450 activities and urea production and quantitation of the mRNA levels of several liver-related genes. Three post-passage age groups were included: 4-d-, 10-d-, and 14-d-old cultures. In comparing flight vs. ground-control cultures 17 h after the space shuttle's return to earth, no differences were found between the cultures with the exception being that some genes were differentially expressed. By light microscopy both young and older cultures, flight and ground, had grown and differentiated normally in the Opticell culture vessels. The PICM-19 cells had grown to approximately 75% confluency, had few signs of apoptosis or necrosis, and had either differentiated into monolayer patches of hepatocytes with biliary canaliculi visible between the cells or into 3-dimensional bile ductules with well-defined lumens. Ultrastructural features between flight and ground were similar with the PICM-19 cells displaying numerous mitochondria, Golgi apparatus, smooth and rough endoplasmic reticulum, vesicular bodies, and occasional lipid vacuoles. Cell-to-cell arrangements were typical in both flight and ground-control samples; biliary canaliculi were well-formed between the PICM-19 cells, and the cells were sandwiched between the STO feeder cells. PICM-19 cells displayed inducible P450 activities. They produced urea in a glutamine-free medium and produced more urea in response to ammonia. The experiment's aim to gather preliminary data on the PICM-19 cell line's suitability as an in vitro model for assessments of liver function in microgravity was demonstrated, and differences between flight and ground-control cultures were minor.

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Altered carbohydrate, lipid, and xenobiotic metabolism by liver from rats flown on Cosmos 1887

Cited by 44 publications

References 19 publications

Upregulation of miR-223 in the rat liver inhibits proliferation of hepatocytes under simulated microgravity

Upregulation of miR-223 in the rat liver inhibits proliferation of hepatocytes under simulated microgravity

Physiological, Pharmacokinetic, and Pharmacodynamic Changes in Space

The effects of space flight and microgravity on the growth and differentiation of PICM-19 pig liver stem cells

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