Mario Congiu

Coordinate regulation of metabolic enzymes and transporters by nuclear transcription factors in human liver disease

Background:  It has been hypothesised, mainly from studies with animal models of liver disease, that the transport of substrates for metabolic enzymes and their subsequent metabolism and elimination in hepatic bile or blood is co‐ordinated, but there is little information on this process in diseased human liver.

THE AFFINITY OF 17α‐HYDROXYPROGESTERONE AND 17α, 20α‐DIHYDROXYPROGESTERONE FOR CLASSICAL MINERALOCORTICOID OR GLUCOCORTICOID RECEPTORS

The displacement of [3H]‐aldosterone, [3H]‐dexamethasone, and [3H]‐cortisol by 17αL‐hydroxyprogesterone, 17αL, 20αL‐dihydroxyprogesterone and 17α, 20β‐dihydroxyprogesterone from ovine cytosol receptors indicates that they do not occupy classical mineralocorticoid or glucocorticoid receptors.

Expression of common housekeeping genes is affected by disease in human hepatitis C virus-infected liver

Background: Comparative gene expression is commonly determined with reference to the expression of a housekeeping gene (HKG), the level of which is assumed to be unregulated. There are little data to date on the effect of disease on the expression of classic HKGs in hepatitis C virus (HCV)‐infected human liver.

Somatostatin centrally inhibits vasopressin secretion during haemorrhage

Somatostatin is a hypothalamic inhibiting factor which has been reported to be involved in the regulation of the secretion of several anterior pituitary hormones. To determine if somatostatin plays a role in the control of vasopressin secretion from the posterior pituitary, we examined the effects of intracerebroventricular infusion of somatostatin-14 and a super-active analogue, cyclo-(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe), on the concentration of plasma vasopressin in response to haemorrhage in conscious sheep. Haemorrhage (15 ml/kg over 15 min) elevated plasma vasopressin. Treatment with either somatostatin-14 or the analogue inhibited the elevation of plasma vasopressin induced by haemorrhage. The inhibition may result from an effect of somatostatin on neurotransmitter afferent inputs to the hypothalamus which trigger vasopressin release during haemorrhage. Our study demonstrates for the first time that somatostatin administered centrally inhibits vasopressin secretion during haemorrhage in the conscious animal.

Augmented plasma renin levels in dehydrated sheep with periventricular lesions

Ablation of tissue in the midline anterior wall of the third ventricle (AV3V) of sheep did not consistently alter baseline plasma renin concentration (PRC) in water replete animals, but caused a greatly augmented increase in PRC in response to water deprivation. PRC might increase in these sheep in order to maintain blood pressure, however it is possible that a central inhibitory influence on renal renin release, operative during dehydration, is disrupted by AV3V-lesions.

The relationships between IFNL4 genotype, intrahepatic interferon-stimulated gene expression and interferon treatment response differs in HCV-1 compared with HCV-3

The biological mechanism underlying the association between IFNL4/IFNL3 polymorphism and peginterferon/ribavirin (PR) response in HCV‐1 is thought to involve differential intrahepatic interferon‐stimulated gene expression. HCV‐3 is more sensitive to PR, but there are no studies of the association between IFNL4 polymorphism, PR treatment response and liver interferon‐stimulated gene expression in HCV‐3.

Effect of the Acute Phase Response Induced by Endotoxin Administration on the Expression and Activity of UGT Isoforms in Rats

To evaluate the effect of endotoxin administration on the glucuronidation of multiple substrates in a rat model. In addition, the effect of endotoxin treatment on selected UGT mRNA levels in the liver and the kidney was also investigated. Male Sprague-Dawley rats (n= 6) received endotoxin (1.6 mg/kg) by intraperitoneal injection. The animals were sacrificed at 6, 12, 24, 48 hr after treatment, and the liver and the kidneys were harvested. Glucuronidation of various substrates (i.e., acetaminophen, estradiol, testosterone, and morphine) was evaluated using prepared tissue microsomes. Real-Time PCR was used to determine mRNA levels of UGT1A1, 1A6, 2B1, and 2B3 in the harvested organs. UGT1A and UGT2B family isoforms were differentially affected by endotoxin treatment. The greatest reduction in glucuronide formation was observed for estradiol-17-glucuronide (-37%) in hepatic microsomes 48 hr after endotoxin administration. Estradiol-3-glucuronide formation was reduced in liver microsomes (466.3+/-71.5 pmol/min/mg vs. 346.9+/-23.2 pmol/min/mg, p < 0.05) but was not significantly altered in the kidney. Similarly, acetaminophen glucuronide formation was decreased in liver but not kidney microsomes. Significant reductions in glucuronide formation were also observed for morphine (-26%) and testosterone (-30%) in septic rats compared to controls. Endotoxin administration was associated with a time-dependent decrease in UGT1A1, UGT1A6, UGT2B1, and UGT2B3 mRNA levels in liver and kidney tissues. These findings demonstrate that both mRNA and activity of UGT isoforms in rats are decreased following endotoxin treatment, although tissue specific effects do also exist.

No increase in the expression of key unfolded protein response genes in HCV genotype 3 patients with severe steatosis

Although hepatic steatosis is common in patients infected with HCV, the mechanisms leading to cellular triglyceride retention are obscure. A role for the Unfolded Protein Response (UPR) has been postulated, either through its activation or dysfunction. In this study we set out to investigate the expression of key UPR genes in HCV genotype 3 patients with moderate to severe steatosis. RNA was extracted from liver obtained by percutaneous biopsy and key genes from the UPR were semi quantified using real-time PCR. We compared values in patients with minimal steatosis to those with high steatosis. Patients with high steatosis were younger (44.6 ± 2.4 vs. 37.4 ± 2.1, p<0.05) and had higher hepatic viral RNA loads (1.00 ± 0.21 vs. 3.98 ± 0.22, p<0.05). We found no significant difference in the expression of UPR genes, except for a small increase in EDEM1 in the high steatosis group (1.00 ± 0.13 vs. 1.38 ± 0.09, p<0.05). In conclusion, despite a four-fold greater concentration of HCV RNA in tissue with a high level of steatosis, we found no change in the expression of key UPR related genes, except for a only a modest up-regulation of EDEM1. Our data does not support a sustained change in expression of UPR genes in the steatogenesis of HCVGT3 infected human liver.