Response of hepatic mitochondrial alpha-glycerophosphate dehydrogenase and malic enzyme to constant infusions of L-triiodothyronine in rats bearing the Walker 256 carcinoma. Evidence for divergent postreceptor regulation of the thyroid hormone response.

Abstract

Aatract. To characterize the hepatic response to L-triiodothyronine (T3) in an experimental nonthyroidal disease, we determined the activity of hepatic mitochondrial a-glycerophosphate dehydrogenase (a-GPD) and cytosol malic enzyme (ME) as a function of the saturation of the nuclear T3 receptor during constant T3 infusions in rats bearing the Walker 256 carcinoma. Groups of control and tumor-bearing rats were infused by minipumps (Alza Corp., Palo Alto, CA) with vehicle, 1.2 or 4.5 Ag T3/100 body wt per day for 3 d. The range for serum T3 was 47.2±4.1 to 165±17.3 ng/dl for the control rats and 13.2±1.3 to 135±14.3 ng/dl for the tumor-bearing rats. Nuclear T3 receptor concentration was between 0.41±0.06 and 0.47±0.02 ng/mg DNA in control rats and was decreased in tumor-bearing rats to between 0.23±0.03 and 0.26±0.03 ng/mg DNA. Nuclear T3 receptor concentrations were not influenced by the T3 infusions. Specifically bound nuclear T3, determined by radioimmunoassay of extracts of isolated nuclei, was decreased nearly 50% in the tumor-bearing rats. However, the calculated percentage saturation of the T3 nuclear receptor remained similar in control and tumor-bearing rats at each level of T3 infusion. Dose-response curves for a-GPD and ME were curvilinear and showed an This work was presented in part at the 59th annual meeting of the American Thyroid Association, New Orleans, Louisiana, October 5-8, 1983. Address reprint requests to Dr. Surks, Montefiore Medical Center. Receivedfor publication 20 December 1983 and in revisedform 18 April 1984.exponential increase in enzyme activity with progressive receptor saturation. In tumor-bearing rats, the activity curves or calculated appearance rate curves for a-GPD were shifted significantly upward and to the left, indicating greater sensitivity to T3, and those of ME were shifted downward and to the right, indicating decreased responsiveness to T3. Our findings suggest that cellular factors result in postreceptor amplification of the a-GPD response and diminution of the ME response to T3 in tumor-bearing rats. Augmentation of the a-GPD response may be a prototype for other hormonal responses that enable the tumor-bearing rat to maintain an apparent euthyroid state in association with decreased serum T3.

c-erb-A mRNA Correlates with T3-Receptor Levels in Liver and Pituitary of Tumor Rats

“…Mean T3 receptor concentration of liver nuclei from tumor rats, 0.35 ± 0.04 fmol/p-g DNA, was 50 ± 6% of that measured in control rats, 0.70 ± 0.10 fmol/p,g DNA. These findings are in accord with previous reports from our laboratory (14). We have also reported that the abundance of TR in anterior pituitary of tumor rats is decreased to nearly the same extent as demonstrated here for liver.…”

“…In rat liver, the activity of two enzymes, mitochondrial a-glycerophosphate dehydrogenase (a-GPD) and cytosolic malic enzyme (ME) are typically induced by T3. In rats bearing the Walker 256 tumor, a-GPD activity revealed heightened sensitivity to induction of T3 whereas the induction of ME activity by T3 was depressed (14). We have also shown similar differential regulation in the anterior pituitary of tumor animals (15).…”

“…One sample of liver was rapidly frozen in liquid nitrogen; another portion was used for preparation of nuclei as previously described (14). Anterior pituitaries were also removed and snap frozen in liquid nitrogen.…”

“…Nuclei that were isolated from liver were used to measure the abundance of TR by incubation with [ IjT3 as previously described (14).…”

“…A related molecule, rat decrease in abundance of this receptor in anterior pituitary and liver of tumor-bearing rats when compared with controls. Differential regulation of thyroid hormone-induced cellular responses has also been demonstrated in these tissues in tumor rats (14,15). Although the differential response to thyroid hormone in tumor rats may be related to events that occur after the formation of hormone-receptor complexes, it is also possible that changes in expression of different receptor forms in thyroidresponsive tissues might explain altered responses to T3 in tumor rats.…”