Menin is a tumor suppressor protein mutated in patients with multiple endocrine neoplasia type 1. We show that menin is essential for canonical Wnt/Bcatenin signaling in cultured rodent islet tumor cells.

Oxidative stress is implicated in the development of non-alcoholic steatohepatitis (NASH). The Nrf2-antioxidant response element pathway protects cells from oxidative stress. Studies have shown that global Nrf2 deficiency hastens the progression of NASH. The purpose of this study was to determine whether long-term hepatocyte-specific activation of Nrf2 mitigates NASH progression. Transgenic mice expressing a constitutively active Nrf2 construct in hepatocytes (AlbCre+/caNrf2+) and littermate controls were generated. These mice were fed standard or methionine-choline-deficient (MCD) diet, a diet used to induce NASH development in rodents. After 28 days of MCD dietary feeding, mice developed significant increases in steatosis, inflammation, oxidative stress, and HSC activation compared with those mice on standard diet. AlbCre+/caNrf2+ animals had significantly decreased serum transaminases and reduced steatosis when compared with the AlbCre+/caNrf2- animals. This significant reduction in steatosis was associated with increased expression of genes involved in triglyceride export (MTTP) and β-oxidation (CPT2). However, there were no differences in the increased oxidative stress, inflammation, and HSC activation from MCD diet administration between the AlbCre+/caNrf2- and AlbCre+/caNrf2+ animals. We conclude that hepatocyte-specific activation of Nrf2-mediated gene expression decreased hepatocellular damage and steatosis in a dietary model of NASH. However, hepatocyte-specific induction of Nrf2-mediated gene expression alone is insufficient to mitigate inflammation, oxidative stress, and HSC activation in this nutritional NASH model.

Ischemia/reperfusion (I/R) injury in liver grafts, initiated by cold preservation and augmented by reperfusion, is a major problem complicating graft quality, post-transplant patient care, and outcomes of liver transplantation (LTx). Kupffer cells (KC) play important roles in I/R injury; however, little is known about their changes during cold preservation. We examined whether pretreatment with carbon monoxide (CO), a cytoprotective product of heme degradation, would influence KC activity during cold storage and protect the liver graft against LTx-induced I/R injury. In vitro, primary rat KC were stimulated for 24 hrs with hypothermia (4°C, 20% O2), LPS, or hypoxia (37°C, 5% O2) with and without CO pretreatment. When exposed to hypothermia, rat KC produced ROS, but not TNF-α or NO. Preincubation of KC with CO upregulated HSP70 and inhibited ROS generation. When liver grafts obtained from donor rats exposed to CO (250 ppm) for 24 hrs were transplanted after 18 hrs cold preservation in UW solution, HSP70 expression in the grafts increased, and serum AST/ALT levels as well as necrotic area and inflammatory infiltrates were significantly reduced after LTx, when compared to control grafts. CO-pretreated liver grafts showed less TNF-α, ICAM-1 and iNOS mRNA upregulation, as well as reduced pro-apoptotic Bax mRNA, cleaved caspase-3 and PARP expressions. Thus, donor pretreatment with CO ameliorates I/R injury associated with LTx, with an increased hepatic HSP70 expression, particularly in KC population.

Background and Aims Hepatic ischemia reperfusion injury (IRI) is a critical component of hepatic surgery. Oxidative stress has long been implicated as a key player in IRI. In this study, we examine the cell-specific role of the Nrf2-antioxidant response element pathway in warm hepatic IRI. Methods Nrf2 KO and WT animals, and novel transgenic mice expressing a constitutively active Nrf2 mutant in hepatocytes (AlbCre+/caNrf2+) and their littermate controls underwent partial hepatic ischemia or sham surgery. The animals were sacrificed 6 hours after reperfusion and their serum and tissue collected for analysis. Results As compared to wild type animals after IR, Nrf2 KO mice had increased hepatocellular injury with increased serum ALT and AST, Suzuki score, apoptosis, an increased inflammatory infiltrate and enhanced inflammatory cytokine expression. On the other hand, AlbCre+/caNrf2+ that underwent IR had significantly reduced serum transaminases, less necrosis on histology, and a less pronounced inflammatory infiltrate and inflammatory cytokine expression as compared to the littermate controls. However, there were no differences in apoptosis. Conclusion Taken together, Nrf2 plays a critical role in our murine model of warm hepatic IRI, with Nrf2 deficiency exacerbating hepatic IRI and hepatocyte specific Nrf2 over-activation providing protection against warm hepatic IRI.

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