The hyperthyroid state is associated with low hepatic glycogen levels, but paradoxically with a high activity of glycogen synthase and low activity of glycogen phosphorylase. We determined the effects of triiodo-L-thyronine (T3) on glycogen synthesis and glycogen synthase activity in rat hepatocytes in vitro. Culture of rat hepatocytes with T3 (100 nM-1 microM) for 16 h-40 h increases glycogen synthesis from glucose and gluconeogenic precursors. The stimulation of glycogen synthesis by T3 was associated with an increase in the activity of glycogen synthase and was additive with the long-term effects of insulin but not with the short-term stimulation of glycogen synthesis by insulin. Culture of hepatocytes with T3 (at concentrations up to 1 microM) did not affect the responsiveness of glycogen synthesis to short-term stimulation by insulin but culture with 10 microM-T3 decreased the responsiveness to insulin without affecting the basal rate. It is suggested that the high activity of glycogen synthase in the hyperthyroid state is due to a direct effect of T3 on the hepatocyte, but the low hepatic glycogen content is probably due to either secondary metabolite and/or endocrine changes or to impaired responsiveness to insulin. T3 may have an anabolic role in the control of hepatic glycogen storage in the euthyroid postprandial state.
The interactions of insulin, growth hormone (somatotropin) and tri-iodothyronine (T3) in the long-term (24 h) regulation of fatty acid and carbohydrate metabolism were studied in hepatocyte primary cultures isolated from normal or hypophysectomized Sprague-Dawley rats. Hepatocytes from hypophysectomized rats had similar rates of palmitate metabolism, but lower rates of ketogenesis, than hepatocytes from normal rats. They also had a lower endogenous triacylglycerol content and lower activities of NADP-linked dehydrogenases than did cells from normal rats. The inhibitions of ketogenesis and gluconeogenesis by insulin were more marked in hepatocytes from hypophysectomized than from normal rats. Insulin caused a 7-10-fold increase in cellular glycogen in hepatocytes from hypophysectomized rats, compared with a 2-3-fold increase in cells from normal rats, and it increased cellular triacylglycerol by 65% in cells from hypophysectomized rats, compared with 11% in cells from normal rats. In hepatocytes from hypophysectomized rats, growth hormone and T3 increased ketogenesis both separately and in combination (12% and 23% respectively; P less than 0.05), whereas in hepatocytes from normal rats only the combination of growth hormone and T3 caused a significant increase in ketogenesis. In cells from hypophysectomized rats, T3 and growth hormone had different effects on carbohydrate metabolism: T3, but not growth hormone, potentiated the anti-gluconeogenic and glycogenic effects of insulin. It is concluded that hypophysectomy increases the responsiveness of hepatocytes to insulin, growth hormone and T3, and that growth hormone and T3 regulate fatty acid and carbohydrate metabolism by different mechanisms.
Plasma growth hormone concentrations are raised in diabetics with poor metabolic control [ l , 21, but whether growth hormone contributes to the metabolic imbalance is not known. Administration of physiological doses of growth hormone in man increases plasma ketone body concentrations [3,4]. This is due partly to increased lipolysis in adipose tissue and thereby increased fatty acid supply to the liver. However, the increase in ketone body concentration does not always parallel the rise in fatty acid concentration, suggesting intrahepatic regulation of ketogenesis [ 31, either directly by growth hormone, or indirectly via secondary endocrine changes.Direct effects of growth hormone on rat hepatocyte suspensions or cultures have been reported, including: acute inactivation of acetyl-CoA carboxylase in hepatocyte suspensions [5]; increased activity of phosphatidate phosphohydrolase after 20 h culture [6]; and decreased activities of various lipogenic enzymes, but induction of glucose-6-phos-Abbreviations used: T,, tri-iodothyronine; MEM, minimum essential medium. phate dehydrogenase after 6 day culture with growth hormone [ 71. Growth hormone also increases glucose transport in hepatocytes from hypophysectomized, but not from normal, rats [8].We examined the effects of human recombinant growth hormone and its interactions with insulin and tri-iodothyronine (T3) on fatty acid metabolism and its partitioning towards mitochondria1 /%oxidation to ketone bodies in rat hepatocyte cultures.Rat hepatocytes were isolated [9] from male Sprague-Dawley rats obtained from Charles River U.K. (body weight: 130-300 g for normal rats and 120-150 g for hypophysectomized) and cultured in minimum essential medium (MEM) containing 5% (v/v) fetal bovine serum in 25 cm2 flasks [lo]. After cell attachment, the medium was replaced by MEM containing 10 nwdexamethasone and the hormones under study: human recombinant methionyl growth hormone (Kabivitrum, Stockholm, Sweden); insulin and 3, 3', 5-tri-iodothyronine (Sigma, St Louis, MO, USA.). Duplicate flasks for each condition were equilibriated with COJair (1 : 19) and incubated at 37°C for 24 h with a change of medium containing fresh hormones at 12 h. After 24 h, the medium was replaced with MEM containing: 0.75 mMpalmitate; 0.5 mM-L-carnitine; 1 mwpyruvate and defatted bovine serum albumin (7.5 mg/ml) and the flasks were incubated for 2 h. On termination of the incubation the medium Table 1. Regulation of fatty acid metabolism by human recombinant growth hormone (hrCH)and T, in cultured hepatocytesHepatocytes were cultured with the hormones indicated, with/without hrGH ( 1 pg/ml). Palmitate metabolism and ketone body formation (acetoacetate and 3-hydroxybutyrate) were determined between 24 and 26 h. Rates are expressed as nmol of substrate metabolized or product formed/h per mg of protein, for metabolites and nmol of product formed/mg of protein for cellular triacylglycerol. Values are means f S.E.M for duplicate flasks from seven cultures. Statistics (paired t-test): *P< 0.05, **P< 0.005 ...
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