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Experiment Information

Experiment Description for: Hepatic Enzyme Adaption in Rats after

Spaceflight (SL3 BSP24)

OBJECTIVES:

Metabolic breakdown of pharmaceutical agents, nutrients, and many

hormones begins in the liver and the numerous hepatic enzymes that

regulate these catabolic functions respond adaptively to

environmental and biochemical changes. The ability to adapt to

microgravity during prolonged space flight requires biochemical

adjustments that follow changes such as increased secretion of

adrenal hormones. This study was to determine whether hepatic enzyme

concentrations change during space flight.

APPROACH:

Livers removed from flight and control animals postflight were

minced, homogenized and centrifuged. The supernatant was removed and

samples were recentrifuged to prepare microsomes and cytosols.

Enzymes were determined by standard spectrophotometric techniques and

glycogen was determined by the anthrone reaction.

RESULTS:

There was a twenty-fold greater glycogen content in livers of animals

after spaceflight than in ground controls, although the enzymatic

basis for this change was not explored. The microsomal protein,

cytochrome P-450, was reduced in the flight tissue (obtained twelve

hours after the Shuttle landed). The assay used measures all forms of

this enzyme; therefore, study should be extended to examine which

forms are altered and the possible metabolic consequences thereof.

Glutathione S-transferase, tyrosine aminotransferase, and cytochrome

b5 were not statistically different in the two groups. To learn

whether these biochemical changes affect drug and nutrient

metabolism, and influence changes observed in other tissues, will be

of both scientific and practical value.

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Curators: Afzal Ahmed and Oliveaux

Responsible NASA Official: Kathy -Throop, Ph.D.

Several NASA centers participate in the Life Sciences Data Archive

project:

Kathy -Throop, Ph.D., LSDA Project Manager

X. Callahan, Ph.D., Data Archive Project Manager, NASA Ames

Research Center (ARC)

Kathy -Throop, Ph.D., Data Archive Project Manager, NASA

Space Center (JSC)

Bridgit O'Hara Higginbotham, Data Archive Project Manager, Kennedy

Space Center (KSC)

Baselined : 12/15/99 Last Updated : 10/20/2000

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Reciprocal Regulation of Glycogen Biosynthesis and Mobilization

Glycogen synthesis and breakdown are controlled tightly by hormonal

action. These involve regulatory kinase cascades, as depicted in

Figure 13.18 for glycogen breakdown. Like gluconeogenesis/glycolysis,

glycogen synthesis/breakdown is reciprocally regulated. For example,

epinephrine inhibits glycogen synthesis at the same time as it

promotes glycogen breakdown.

Glycogen synthase is the primary regulatory enzyme in glycogen

synthesis. Like glycogen phosphorylase, the enzyme that breaks down

glycogen, glycogen synthase exists in phosphorylated and

dephosphorylated states. Some of the

phosphorylations/dephosphorylations are catalyzed by the same protein

kinases and phosphatases that regulate glycogen breakdown. Figure

16.11 illustrates that the cAMP-stimulated kinase regulatory cascade

for both glycogen synthesis and breakdown pathways is the same. The

primary difference lies in the effect of phosphorylation on the

primary regulatory enzymes, glycogen synthase (made less active) and

glycogen phorphorylase a (made active).

When glycogen synthase is phosphorylated, its activity depends upon

the presence of glucose-6-phosphate. It is thus called the dependent

form. The unphosphorylated form of glycogen synthase acts

independently of glucose-6-phosphate and is called the independent

form.

Note in Figure 16.11 that active protein kinase can phosphorylate

glycogen synthase directly, in addition to the phosphorylation by

synthase-phosphorylase kinase (also called phosphorylase b kinase).

Dephosphorylation of glycogen synthase and glycogen phosphorylase

reverses the effects of phosphorylation. This converts glycogen

synthase to the independent form and glycogen phosphorylase to a less

active form. The primary enzyme responsible for dephosphorylating the

glycogen metabolism enzymes is phosphoprotein phosphatase (PP-1). It

is regulated by another protein called phosphoprotein phosphatase

inhibitor (PI-1). PI-1 is also phosphorylated by active protein

kinase. When phosphorylated, PI-1 inhibits PP-1.

Thus, cAMP stimulates a kinase cascade that phosphorylates the

regulatory enzymes of glycogen metabolism. It simultaneously

activates PI-1, which converts PP-1 to the inactive form. Conversely,

action of insulin stimulates phosphatase activity in cells,

completely reversing the kinase cascade and reversing the preferred

activities of the glycogen metabolism enzymes.

The bottom line:

1. Epinephrine and glucagon stimulate glycogen breakdown. They do

this via stimulating production of cAMP, which activates a kinase

(phosphorylation) cascade, which activates glycogen phosphorylase,

converts glycogen synthase to the dependent form, and inhibits

phosphoprotein phosphatase.

2. Insulin stimulates dephosphorylation, which activates

phosphoprotein phosphatase, which reverses the activities of the

glycogen metabolism, converting glycogen synthase to the independent

form and glycogen phosphorylase to the less active form.

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See also: Reciprocal Regulation, Kinase Cascade (from chapter 13),

Glycogen Breakdown Regulation,

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----------The adrenal glands

The adrenal glands lie above the kidney and are therefore sometimes

referred to by the older term suprarenal glands. They have a cortex

and a medulla. The former synthesizes and secretes steroid hormones

that are essential for life, but it is not under autonomic control.

The {adrenals} adrenal medulla, on the other hand, is innervated by

sympathetic preganglionic neurons. Within the adrenal medulla are

{adrenals} chromaffin cells, which are homologous to sympathetic

neurons and, like sympathetic neurons, are developed from embryonic

neural crest cells. Chromaffin cells produce epinephrine (adrenalin)

and, to a much lesser extent, norepinephrine as well as other

chemicals such as chromogranins, enkephalins, and neuropeptide Y—all

of which are released into the bloodstream and act as hormones.

Epinephrine, in particular, affects many different types of tissues

throughout the body and has a particularly potent effect on cells

that possess b -adrenergic receptors.

The release of epinephrine prevents {hypoglycemia} hypoglycemia (low

blood sugar), through the following mechanism. By binding to a 2-

adrenergic receptors embedded in the hormone-releasing cells of the

{pancreas} pancreas, epinephrine inhibits the release of insulin.

Since insulin promotes the absorption of glucose from the bloodstream

into liver, skeletal muscle, and fat cells, inhibition of its release

results in a greater amount of glucose that is available for entry

into the brain. In addition, by binding to certain b -adrenergic

receptors, epinephrine stimulates the release of glucagon, a

pancreatic peptide hormone that acts in the liver to convert glycogen

to glucose. Under emergency conditions, epinephrine causes even more

widespread effects on glucose metabolism. Glycogen in the liver and

skeletal muscle is broken down to glucose, fat held in adipose cells

is converted to fatty acids and glycerol, and production of glucose

and ketone bodies ( b -hydroxybutyric acid, acetoacetic acid) is

increased in the liver. All these substances can be used as energy

sources for the body.

The cardiovascular system