IPGTT was performed after a 5-hour fast by injecting 1 g/kg glucose intraperitoneally. and the resulting matrices were examined for collagen cross-linking. == Results == Wild-type mice on a hightrans-fat diet had 80% more hepatic collagen thanHif1a-/-hepmice (2. 21 g collagen/mg liver tissue, versus 1 . 23 g collagen/mg liver tissue, p = 0. 03), which was confirmed by Sirius red staining. Body weight, liver weight, mean hepatic triglyceride content, and fasting insulin were similar between groups. Culture media from wild-type mouse hepatocytes exposed to hypoxia allowed for avid collagen cross-linking, but very little cross-linking was seen when hepatocytes were exposed to normoxia, or when hepatocytes fromHif1a-/-hepmice were used in hypoxia or normoxia. == Conclusions == Hepatocyte HIF-1 mediates an increase in liver fibrosis in a mouse model of NAFLD, perhaps due to liver tissue hypoxia in hepatic steatosis. HIF-1 is necessary for collagen cross-linking in anin vitromodel of fibrosis. == Introduction Rabbit Polyclonal to OR2G3 == Non-alcoholic fatty liver disease (NAFLD) is the most common disease of the liver in the West [1], and is the hepatic manifestation of the metabolic syndrome [2]. Some patients with NAFLD will see a progression of their disease to a phenotype of liver inflammation and fibrosis ( non-alcoholic steatohepatitis, or NASH). In particular, hepatic fibrosis in NASH appears to lead to poorer outcomes, including need for liver transplantation and overall Bay 65-1942 mortality [3]. Obstructive sleep apnea (OSA) is a common sleep disorder with an estimated prevalence of at least 45% in the general population [4]. The airway collapse that is thesine Bay 65-1942 qua nonof OSA has several downstream effects, including Bay 65-1942 intermittent oxygen desaturations, arousals from sleep, and significant intrathoracic pressure swings [5]. In the last decade, a number of associative studies have noted that markers of liver injury and fibrosis in NAFLD are more pronounced in patients with severe OSA, independent of obesity, and this appears primarily related to the burden of nocturnal hypoxia [611]. This observation has now been made in several patient populations, both adult and pediatric. Moreover, chronic intermittent hypoxia (IH) mimicking the oxygen profile of patients with severe OSA in mice on a high fat diet also induces progression of hepatic steatosis to liver fibrosis and worsened hepatocellular injury [12, 13]. Despite the increasingly robust evidence of an associative link between NAFLD progression and OSA severity, there has been comparatively little investigation to suggest a mechanism which may tie together any aspect of these two illnesses. In NAFLD, hepatic stellate cell activation has been proposed as a crucial step in the progression toward hepatic fibrosis, and hepatocyte injury and apoptosis have been noted in this progression as well [14, 15]. However , little data is available about the importance of tissue hypoxia in the hepatocyte in NAFLD. Emerging evidence has demonstrated that liver hypoxia may be a key mediator of several diseases of the liver [16], and our approach was to consider the possibility that hepatocyte hypoxia may be a key mechanistic step needed for OSA to impact the progression of Bay 65-1942 NAFLD. A number of recent publications have demonstrated that tissue hypoxia, among other stimuli, increases expression of the fibrogenic enzyme lysyl oxidase (LOX) [17, 18], regulated by hypoxia inducible factor-1 (HIF-1) [17, 19, 20]. LOX is a secreted amine oxidase which catalyzes the formation of covalent cross-links between collagen fibers in the extracellular matrix.