Octreotide attenuates liver fibrosis by inhibiting hepatic heme oxygenase-1 expression

Abstract

The aim of the present study was to investigate the effects of octreotide treatment on hepatic heme oxygenase-1 (HO-1) expression, together with the influence of altered hepatic HO-1 expression levels on hepatic function and fibrosis in bile duct-ligated rats. The rats were divided randomly into sham, cirrhotic, cobalt protoporphyrin and octreotide treatment groups. The expression levels of hepatic HO-1 mRNA were measured by reverse-transcription polymerase chain reaction, while the protein expression was determined by western blotting and immunohistochemical analysis. Hematoxylin and eosin, and Van Gieson’s staining, along with determination of the hydroxyproline content in the liver, were performed to determine the degree of liver fibrosis. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and carboxyhemoglobin (COHb) in arterial blood, and the mean arterial pressure and portal vein pressure were also measured. As compared with the sham group, hepatic HO-1 mRNA and protein expression levels, serum levels of ALT, AST and TBIL, COHb in arterial blood, hydroxyproline and collagen type I content were all significantly increased in the cirrhotic group. As compared with the cirrhotic group, the octreotide-treated group exhibited significantly reduced hepatic HO-1 expression levels, serum levels of ALT, AST and TBIL, COHb in arterial blood and the extent of hepatic fibrosis, whereas the cobalt protoporphyrin group exhibited significantly increased hepatic HO-1 expression levels, as well as aggravated hepatic function and fibrosis (P<0.05). In conclusion, octreotide inhibited hepatic HO-1 overexpression in cirrhotic rats, reduced hepatic HO-1 expression levels to relieve liver injury and attenuated liver fibrosis.

Activation of necroptosis in human and experimental cholestasis

“…Indeed, HO-1 overexpression significantly exacerbates liver fibrosis and portal hypertension induced by chronic BDL in rats. 25 , 33 , 34 Further, and in agreement with our results, chronic HO-1 overexpression directly promotes hepatic iron accumulation in BDL rats, 25 , 37 whereas iron chelation diminishes liver fibrosis. 37 We found that RIP3 −/− primary hepatocytes displayed increased iron levels compared with WT hepatocytes, being iron content modulated by HO-1 activity.…”

“…HO-1 is a well-established stress-inducible enzyme, 32 found upregulated in the liver of BDL rats. 25 , 33 , 34 Overexpression of HO-1 can protect steatotic livers from ischemia–reperfusion injury in rats 35 and from chronic ethanol-induced liver injury in mice. 36 Interestingly, HO-1 upregulation reduces hepatic RIP3 expression in mice upon chronic ethanol feeding and protects primary rat hepatocytes from necroptosis induced by co-exposure of ethanol and tumor necrosis factor- α (TNF- α ).…”

“…These findings suggest a mechanistic loop involving HO-1 and RIP3 that is warranted to be further explored in the future. Nevertheless, detrimental effects associated with chronic HO-1 upregulation could also be present in RIP3 −/− mice following BDL; 25 , 33 , 34 RIP3 deficiency exacerbated cholestasis and jaundice 14 days after BDL, as evidenced by increased levels of bilirubin and AP, likely due to sustained overexpression of HO-1. Indeed, HO-1 is a rate-limiting enzyme in the bilirubin metabolism and it directly worsens hyperbilirubinemia in BDL rats.…”

Cyclooxygenase-2 up-regulates hepatic somatostatin receptor 2 expression

“…Additionally, SST and its analogues protect against liver cirrhosis 3 . The SST analogue octreotide alleviates liver cirrhosis by directly inhibiting the synthesis of alpha-smooth muscle actin (α-SMA) and collagens in hepatic stellate cells (HSCs) 4 – 6 . Furthermore, SST and its analogues reduce splanchnic blood flow and decrease portal vein pressure by inducing the contraction of peripheral vessels, inhibiting the secretion of vasodilatory peptides and the contraction of HSCs 7 – 9 .…”

Endogenous carbon monoxide downregulates hepatic cystathionine-γ-lyase in rats with liver cirrhosis

“…Hyperdynamic circulation, which is secondary to the presence of systemic vasodilation, is an important factor in the aggravation and persistence of portal hypertension ( 1 ). Numerous mechanisms are involved in the development of systemic vasodilation, including increased synthesis of nitric oxide (NO) and carbon monoxide (CO) and the activation of K ATP channels in the systemic and splanchnic arterial circulation ( 2 ). Previous studies have demonstrated that the hepatic heme oxygenase-1 (HO-1)/CO system ( 3 ) and NO/nitric oxide synthetase activity are overexpressed in rats with cirrhosis and contribute to portal hypertension ( 4 )…”