Effects of plasma exposure on cultured hepatocytes: Implications for bioartificial liver support

Matthew, Howard W.T.; Sternberg, J.; Stefanovich, Peter; Morgan, Jeffrey R.; Toner, Mehmet; Tompkins, Ronald G.; Yarmush, Martin L.

doi:10.1002/(sici)1097-0290(19960705)51:1<100::aid-bit12>3.0.co;2-u

Cited by 34 publications

(27 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At the same time, lipid accumulation is a well-recognized response of the liver to various forms of toxic injury. 3 These two functions are clinically relevant indicators of hepatic performance provided by a BAL device. In previous studies, elevated intracellular TG accumulation and reduced urea synthesis were simultaneously observed in hepatocytes preconditioned in high insulin concentrations before being cultured in plasma.…”

Section: Relationship Between Lipid Accumulation and Urea Synthesis Imentioning

confidence: 99%

“…2 Previously, it was found that hepatocytes exposed to plasma accumulated high levels of lipids and correspondingly had a reduced rate of urea synthesis. 3 In subsequent investigation, it was found that we could confer resistance to this lipid-accumulating effect in primary rat hepatocytes and downregulation of urea synthesis by culturing the cells in medium containing physiological, as opposed to supraphysiological, levels of insulin during the preconditioning period, before exposing them to human plasma supplemented with amino acid. 4 These findings are consistent with the notion that preconditioning of hepatocytes presets the metabolic machinery of these cells and thereby directly affects their ensuing metabolic behavior during culturing in plasma.…”

Section: Introductionmentioning

confidence: 99%

“…Elevated levels of intracellular TG and fatty acids have been observed in type 2 diabetes. 3 The presence of intracellular lipids increases the risk of lipid peroxidation and cellular membrane damage. 7 In the current study, in addition to the five genes of the urea cycle enzymes, we were also particularly interested in examining the expression levels of several genes and transcription factors related to enzymes involved in fatty acid metabolism.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Insulin Concentration during Preconditioning Mediates the Regulation of Urea Synthesis during Exposure to Amino Acid-Supplemented Plasma

Zheng

Yarmush

Chan³

2004

Tissue Engineering

View full text Add to dashboard Cite

Understanding the effects of preconditioning on cellular metabolism is important in providing insight into how cells and tissues may behave when confronted with alterations in their environment. Previously, elevated accumulation of lipids and a correspondingly reduced rate of urea synthesis were found in primary heptocytes preconditioned in culture medium containing high levels of insulin and then exposed to plasma. Subsequent studies found that preconditioning primary hepatocytes in medium containing low levels of insulin before exposure to plasma supplemented with amino acids was able to confer resistance to the lipid-accumulating effect of plasma exposure and restored urea synthesis. In the current study, we investigated the effects of insulin preconditioning and amino acid supplementation on the gene expression profile of the urea cycle and fatty acid metabolism enzymes. We found that insulin preconditioning mediates the effects of amino acids in the plasma exposure period on urea synthesis. Urea synthesis is regulated by insulin and amino acids through both short-term and long-term control. Possible mechanisms of long-term control through transcriptional regulation of urea synthesis by insulin, amino acids, and enzymes and transcription factors associated with lipid metabolism are discussed.

show abstract

Section: Relationship Between Lipid Accumulation and Urea Synthesis Imentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Insulin Concentration during Preconditioning Mediates the Regulation of Urea Synthesis during Exposure to Amino Acid-Supplemented Plasma

Zheng

Yarmush

Chan³

2004

Tissue Engineering

View full text Add to dashboard Cite

show abstract

“…This loss of function may be especially important in toxicological and metabolic studies, where the time scale for responses may exceed the time scale for loss of hepatocyte function. To overcome these current limitations, many culture strategies have been developed to simulate the environment of normal hepatic structures, such as cultures on porous membrane gels (Ostrovidov et al 2004) stacked cultures (Sudo et al 2005), co-cultures with nonhepatic cells (Miyazawa et al 2005;Scott et al 2005), threedimensional (3D) cultures of hepatocyte aggregates known as spheroids (Glicklis et al 2004), sandwich cultures (Farghali et al 1994;Langsch and Bader 2001;Matthew et al 1996) Electronic supplementary material The online version of this article (doi:10.1007/s10544-016-0079-6) contains supplementary material, which is available to authorized users. and cultured with Extra cellular matrix overlay (Sidhu et al 1994).…”

Section: Introductionmentioning

confidence: 99%

Lab on a chip-based hepatic sinusoidal system simulator for optimal primary hepatocyte culture

Choi

Kim

Lee

et al. 2016

Biomed Microdevices

View full text Add to dashboard Cite

Primary hepatocyte cultures have been used in studies on liver disease, physiology, and pharmacology. While they are an important tool for in vitro liver studies, maintaining liver-specific characteristics of hepatocytes in vitro is difficult, as these cells rapidly lose their unique characteristics and functions. Portal flow is an important condition to preserve primary hepatocyte functions and liver regeneration in vivo. We have developed a microfluidic chip that does not require bulky peripheral devices or an external power source to investigate the relationship between hepatocyte functional maintenance and flow rates. In our culture system, two types of microfluidic devices were used as scaffolds: a monolayer- and a concave chamber-based device. Under flow conditions, our chips improved albumin and urea secretion rates after 13 days compared to that of the static chips. Reverse transcription polymerase chain reaction demonstrated that hepatocyte-specific gene expression was significantly higher at 13 days under flow conditions than when using static chips. For both two-dimensional and three-dimensional culture on the chips, flow resulted in the best performance of the hepatocyte culture in vitro. We demonstrated that flow improves the viability and efficiency of long-term culture of primary hepatocytes and plays a key role in hepatocyte function. These results suggest that this flow system has the potential for long-term hepatocyte cultures as well as a technique for three-dimensional culture.

show abstract

“…[8][9][10] Furthermore, this decrease can be prevented by supplementation of the plasma with hormones and amino acids. 11 While plasma effects on hepatocyte secretory functions have been extensively studied, currently little is known of the effects of plasma on hepatocyte cytochrome P450 (CYP) activities.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Maintenance of Cytochrome P450 Activities by Rat Hepatocyte/3T3 Cell Co-cultures in Heparinized Human Plasma

et al. 2001

View full text Add to dashboard Cite

Little information on the effect of plasma on hepatocyte cytochrome P450 (CYP) activities is currently available. We characterized the effect of plasma on CYPs of hepatocyte-mesenchymal cell co-cultures, which exhibit stable liver specific functions and may be potentially useful for bioartificial liver design. Rat hepatocyte-mouse 3T3-J2 cell co-cultures were maintained for 6 days in medium, and then switched to heparinized human plasma containing 3-methylcholanthrene (3MC; 2 microM), phenobarbital (PB; 1 mM), or no inducer for up to 7 days. CYP activities were measured in situ based on the o-dealkylation of ethoxy- (EROD), methoxy- (MROD), pentoxy- (PROD), or benzyloxy- (BROD) resorufin. Plasma alone increased PROD/BROD but not EROD/MROD. The endogenous inducer was in the high molecular weight fraction (>5 kD) of plasma and inhibited by >5 nM okadaic acid and >10 microM dibutyryl cyclic AMP, two inhibitors of PB-inducible CYPs. Furthermore, plasma increased CYP1A1 and CYP2B1/2 mRNA levels. In plasma, 3MC induced EROD/MROD to about 60% of the level induced in culture medium while PB induced PROD/BROD that were three- to 10-fold above levels induced in medium. CYP activities decreased between days 2 and 7 of plasma exposure, but were enhanced by plasma supplementation with amino acids, insulin, glucagon, and hydrocortisone.

show abstract

Effects of plasma exposure on cultured hepatocytes: Implications for bioartificial liver support

Cited by 34 publications

References 34 publications

Insulin Concentration during Preconditioning Mediates the Regulation of Urea Synthesis during Exposure to Amino Acid-Supplemented Plasma

Insulin Concentration during Preconditioning Mediates the Regulation of Urea Synthesis during Exposure to Amino Acid-Supplemented Plasma

Lab on a chip-based hepatic sinusoidal system simulator for optimal primary hepatocyte culture

Long-Term Maintenance of Cytochrome P450 Activities by Rat Hepatocyte/3T3 Cell Co-cultures in Heparinized Human Plasma

Contact Info

Product

Resources

About