Hypoxia-inducible factor-1 is a determinant of lobular structure and oxygen consumption in the liver.

OBJECTIVE: Hypoxia-inducible factor is a hypoxia-responsive transcriptional factor that controls the expression of proteins contributing to homeostatic responses to hypoxia. Spatial heterogeneity of tissue oxygenation has been postulated as a determinant of structure and function of hepatic lobules, although its molecular mechanisms remain unknown. This study aimed to examine the role of HIF-1 expressed in hepatocytes in regulation of hepatic microcirculation. METHODS: We have generated mice harboring a floxed HIF-1α allele, and employed the albumin-Cre transgenic line to inactivate the gene site-specifically in hepatocytes. RESULTS: Intravital observation of the hepatic microcirculation revealed extension of hepatic lobules in HIF-1α-deficient mice. Measurement of microvascular diameter, velocity, and local oxygen tension by laser-assisted phosphorimetry showed that the oxygen consumption in the lobules of HIF-1α-deficient mice was greater than that in those of control mice. Isolated hepatocytes from HIF-1α-deficient mice also stimulated oxygen consumptions with increased contents of mtDNA. Overexpression of HIF-1α decreased the expression of PGC-1α mRNA, whereas the knockdown of the HIF-1α gene increased it, suggesting that HIF-1 regulates cellular respiration through mitochondrial biogenesis. CONCLUSIONS: Our results suggest that constitutive expression of HIF-1α in hepatocytes acts as a determinant of hepatic lobular structure and oxygen consumption by changing mitochondrial contents.

[Pathological complete response in advanced gastric carcinoma by S-1/CDDP combination chemotherapy].

A59 -year-old woman was referred to our hospital for a close examination and treatment of an advanced gastric carcinoma. A physical examination and CT scan showed that the right cervical and axillar lymph nodes were swelling, and a histopathological examination of the axillar lymph node revealed metastatic growth of the gastric carcinoma (Stage IV). Then, we started S-1/CDDP combination chemotherapy. S-1 (80 mg/m2/day)was orally administered for 3 weeks followed by 2 weeks of rest, and CDDP (60 mg/m2) was administered by drip on day 8. Since the distant metastases were greatly reduced after 6 courses of combination therapy, a distal gastrectomy with lymph nodes dissection (D2) was performed. Histopathological examination of the resected tissues revealed no residual cancer cells, suggesting a pathologically complete response. The clinical course after the operation went well without any complications, and the patient is alive with no evidence of recurrence 1 year after surgery. S-1/CDDP combination chemotherapy appears to be one of the effective treatments for advanced gastric carcinoma.

HIF-1alpha is necessary to support gluconeogenesis during liver regeneration.

Coordinated recovery of hepatic glucose metabolism is prerequisite for normal liver regeneration. To examine roles of hypoxia inducible factor-1alpha (HIF-1alpha) for hepatic glucose homeostasis during the reparative process, we inactivated the gene in hepatocytes in vivo. Following partial hepatectomy (PH), recovery of residual liver weight was initially retarded in the mutant mice by down-regulation of hepatocyte proliferation, but occurred comparably between the mutant and control mice at 72h after PH. At this time point, the mutant mice showed lowered blood glucose levels with enhanced accumulation of glycogen in the liver. The mutant mice exhibited impairment of hepatic gluconeogenesis as assessed by alanine tolerance test. This appeared to result from reduced expression of PGK-1 and PEPCK since 3-PG, PEP and malate were accumulated to greater extents in the regenerated liver. In conclusion, these findings provide evidence for roles of HIF-1alpha in the regulation of gluconeogenesis under liver regeneration.

Carbon monoxide as a guardian against hepatobiliary dysfunction.

Carbon monoxide (CO) generated through the reaction of heme oxygenase (HO) has attracted great interest in regulation of hepatobiliary homeostasis. The gas generated by HO-2 in the hepatic parenchyma can modestly activate soluble guanylate cyclase (sGC) expressed in hepatic stellate cells in a paracrine manner and thereby constitutively relax sinusoids. Kupffer cells express HO-1, the inducible isozyme, even under normal unstimulated conditions and constitutes approximately 30% of the total HO activity in this organ. Upon exposure to a variety of stressors such as cytokines, endotoxin, hypoxia and oxidative stress, the liver induces HO-1 and over-produces CO. The stress-inducible CO has been shown to guarantee ample blood supply during detoxification of heme and thus to play a protective role in the liver. However, molecular mechanisms by which CO serves as a protectant for hepatocytes, the cells expressing little sGC, remain to be solved. Previous observation suggested that CO modulates intracellular calcium mobilization through inhibiting cytochrome P-450 activities and thereby maintain stroke volume of bile canalicular contraction in cultured hepatocytes. CO also stimulates mrp2-dependent excretion of bilirubin-IXalpha and helps heme catabolism. Although a direct molecular target responsible for the latter event remains unknown, such properties of CO could support xenobiotic metabolism through its actions on sinusoidal hemodynamics and hepatobiliary systems.