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The usual increase in the activity of liver fatty-acid synthetase that occurs on refeeding of a fat-free diet to previously fasted rats is abolished in diabetic animals. Insulin specifically restores this increase by enhancement of the rate of synthesis of fatty-acid synthetase. However, glucagon and cyclic AMP inhibit the increase in the activity of fatty-acid synthetase. Therefore, the concentration of fatty-acid synthetase in rat liver is under the control of the relative concentrations of insulin and glucagon.

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Diurnally varying activity of hepatic jB-hydroxy-fl-methylglutaryl coenzyme A reductase (EC 1.1.1.34) was decreased to very low levels in hypophysectomized rats with no discernable diurnal rhythm retained. Administration of triiodothyronine (100 jg/100 g of body weight) produced a supranormal level of reductase activity, about 3-4 times the highest activity found in normal rats. 0-Hydroxy-#-methylglutaryl coenzyme A (HMG-CoA) reductase (EC 1.1.1.34) catalyzes the reduction of HMG-CoA to mevalonate, which is the first committed step in the pathway of cholesterol biosynthesis. This reaction has been established as rate-limiting in the over-all conversion of acetate to cholesterol (1, 2). Indeed, changes in HMG-CoA reductase activity accurately reflect changes in the rate of cholesterol synthesis (3, 4). Interestingly, the activity of the reductase undergoes daily changes of as much as 10-fold (5-8). The normal diurnal rise in reductase activity has been shown to be due to an increase in the rate of enzyme synthesis (9). Recently, we have shown (10) that the activity of HMGCoA reductase was stimulated markedly by insulin treatment. We have further demonstrated that reductase activity was reduced to low levels in diabetic rats with only a negligible diurnal rhythm present seven days after the onset of diabetes (11). Administration of insulin restored the activity to nearly normal levels within 2 hr. Other hormones that have been implicated in stimulating cholesterol biosynthesis are thyroid hormones (12, 13) and norepinephrine (14). Guder et al. (13) have shown that hepatic HMG-CoA reductase activity was decreased to less than 50% of normal in hypothyroid rats (produced by 13l1 treatment). A single injection of triiodothyronine (T3) to these hypothyroid rats restored the activity to that of normal animals within 48 hr. In hypophysectomized rats, hepatic cholesterogenesis was reduced to even lower levels (15) than in hypothyroid rats.In this communication we demonstrate that hepatic HMGCoA reductase activity is markedly lowered in hypophysectomized rats with no detectable diurnal rhythm present. Administration of T3 to these animals increases reductase activity to a supranormal level (3-4 times the highest level found in normal rats). MATERIALS AND METHODS Materials. iTriiodothyronine (T3) and [3-14C]0-hydroxy-,-methylglutaric acid were purchased from Sigma Chemical and New England Nuclear Corp., respectively. Other chemicals were of reagent grade.[s-'4C ]b-Hydroxy-g-methylglutaric acid was converted to the anhydride by the dicyclohexylcarbodiimide method of Goldfarb and Pitot (16). The coenzyme A ester was prepared from the anhydride as described by Hilz et al. (17) and then purified by descending paper chromatography on Whatman 3 MM with isobutyric acid-concentrated ammonia-0.1 M EDTA (pH 4.5)-H20 (124:5:2:75) as the solvent system. Treatment of Animals. Young adult male albino rats weighing 140-160 g were purchased from Holtzman. Animals were hypophysectomized by Altech Laboratories of Madison, Wisc. The h...

1. The metabolism of 5,6-monoepoxyvitamin A aldehyde in the rat was found to be identical with that of vitamin A aldehyde. It promptly alleviated all the symptoms of vitamin A deficiency and promoted the growth of the vitamin A-deficient rats. 2. When administered orally, 5,6-monoepoxyvitamin A aldehyde was reduced to the corresponding alcohol in the intestine and esterified before being transported to the liver for storage. 3. 5,6-Monoepoxyvitamin A aldehyde was not converted into the furanoid form, 5,8-monoepoxyvitamin A aldehyde, during passage through the stomach. 4. Intraperitoneal administration of 5,6-monoepoxyvitamin A aldehyde led to the accumulation of 5,6-monoepoxyvitamin A in the liver and other tissues. Subcutaneous administration of this compound alleviated all the symptoms of vitamin A deficiency. 5. The small intestine is the major, if not the only, site for the metabolic reduction of 5,6-monoepoxyvitamin A aldehyde and its subsequent esterification. 6. It was demonstrated that the rat possesses the necessary enzymes for the reduction and oxidation of 5,6-monoepoxyvitamin A aldehyde to the corresponding alcohol and acid as well as the esterification of 5,6-monoepoxyvitamin A alcohol to its palmitate. These metabolic conversions were shown to be as efficient as those of vitamin A aldehyde and alcohol. 7. 5,6-Monoepoxyvitamin A aldehyde possesses a biological potency 108% that of all-trans vitamin A acetate. 8. A new visual pigment with lambda(max.) 480mmu, along with natural rhodopsin, was isolated from the retinas of rats maintained on 5,6-monoepoxyvitamin A aldehyde. 9. Oral administration of 5,8-monoepoxyvitamin A aldehyde to vitamin A-deficient rats led to the accumulation of 5,8-monoepoxyvitamin A in the liver and other tissues. Enzymic reduction and oxidation of 5,8-monoepoxyvitamin A aldehyde to its alcohol and acid, as well as the esterification of the alcohol, were demonstrated.

Piperine, a bioactive alkaloid, is known to have anticancer activities. Hence, in this study, the effectiveness of piperine pretreatment as a strategy for radio‐sensitizing colorectal adenocarcinoma cell line (HT‐29) was analyzed. For this, HT‐29 cells were pretreated with piperine (12.5 and 25 µg/mL) and exposed to γ‐radiation (1.25 Gy) and analyzed for various effector pathways to elucidate the possible mode of action in comparison to individual treatments. The proliferation efficiency of the cells was analyzed by trypan blue dye exclusion assay and MTT assay. The synergistic effects of the combination treatment were analyzed with compuSyn software. Downstream signaling pathways leading to apoptosis were studied using flowcytometry, immunofluorescence, and immunoblot assays. It was observed that combination treatment arrested HT‐29 cells at G2/M phase nearly 2.8 folds higher than radiation treatment alone, inducing the radio‐resistant cells to undergo apoptosis through mitochondria‐dependent pathway. In addition, activation of caspase‐3 and cleavage of poly(ADP‐ribose) polymerases‐1, the key molecular events in apoptotic signaling, were significantly enhanced. Activation of estrogen receptor beta (ERβ), a nuclear hormone transcription factor promoting tumor suppression represents a novel clinical advance towards management and prevention of cancers. Interestingly, the expression of ERβ was increased in the cells treated with piperine. In conclusion, piperine pretreatment enhances radio‐sensitization in HT‐29 cells by inducing the cells to undergo apoptosis hence, can be used as a classic candidate for colon cancer sensitization towards radiotherapy. Practical Application Piperine induces enhanced radiosensitization of colon cancer cell line (HT‐29) by interfering with the cancer cell line proliferation, DNA damage, and apoptosis.