LPS Increases Hepatic HIF-1α Protein and Expression of the HIF-1-Dependent Gene Aldolase A in Rats

Scharte, Marion; Han, Xianonan; Uchiyama, Takashi; Tawadrous, Zakaria S.; Delude, Russell L.; Fink, Mitchell P.

doi:10.1016/j.jss.2006.05.027

Cited by 19 publications

(15 citation statements)

References 25 publications

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“…Indeed, HIF-1a, considered as an important regulator of profibrotic and vasoactive mediators in hypoxic hepatocytes, mediates the increased expression of ALDOLASE-A in endotoxemic rats. 52,53 On the other hand, ALDOLASE-A, usually absent in the adult liver, might be an early signal that precedes neoplastic transformation and development of hepatocellular carcinoma, which occurs in some very advanced stages of NASH. 54 Worthy of further studies is the hepatic expression level of EPHRIN-A1 and its receptor during dietinduced NAFLD, because of the many cellular functions that these proteins pursue in physiological and pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease

Alisi

Sacco

Bruscalupi

et al. 2011

Laboratory Investigation

178

116

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Nonalcoholic fatty liver disease (NAFLD) is an emerging disease with a broad spectrum of liver conditions. The complex molecular pathogenesis of NAFLD is still unclear. In this study, we conducted an analysis of microRNA (miRNA) expression profiles in liver of rats made NAFLD by different diets. To this aim, Sprague-Dawley rats were fed ad libitum for 3 months with different diets: standard diet (SD), diet enriched in fats and low in carbohydrates (HFD), SD with high fructose (SD-HF) and diet with high levels of fats and fructose (HFD-HF). Our results demonstrated that the treatment with different dietetic regimens caused a significant increase of the body weight and the alteration of some metabolic parameters compared with control animals, as well as various liver injuries. The miRNAs analysis showed the significant downregulation of three miRNAs (miR-122, miR-451 and miR-27) and the upregulation of miR-200a, miR-200b and miR-429 in HFD, SD-HF and HFD-HF rats. Besides, miR-21 expression was significantly decreased only in fructose-enriched diets. These miRNAs target molecules involved in the control of lipid and carbohydrate metabolism, signal transduction, cytokine and chemokine-mediated signaling pathway and apoptosis. Western blot analysis of PKCd, LITAF, ALDOLASE-A, p38MAPK, PTEN, LIPIN1, EPHRIN-A1, EPHA2 and FLT1 showed a diet-induced deregulation of all these proteins. Interestingly, the expression pattern of LITAF, PTEN, LIPIN1, EPHRIN-A1, EPHA2 and FLT1 might be well explained by the trend of their specific mRNAs, by potentially regulatory miRNAs, or both. In conclusion, we highlight for the first time the potential involvement of novel determinants (miRNAs and proteins) in the molecular pathogenesis of diet-induced NAFLD.

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Section: Discussionmentioning

confidence: 99%

Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease

Alisi

Sacco

Bruscalupi

et al. 2011

Laboratory Investigation

178

116

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“…There is evidence that the relationship between HIF-1 activation and inflammation appears to be bidirectional since numerous studies have shown that HIF-1 is a central regulator of inflammation and innate immunity (50), whereas at the same time proinflammatory mediators such as TNF-␣, IL-1␤, nitric oxide, and LPS have been shown to induce HIF-1␣ expression in cells, including enterocytes, even under normoxic conditions (29,41,58,59). In this context, our findings suggest that the diminished intestinal TNF-␣, IL-1␤, and iNOS responses as well as the reduced pulmonary IL-1␤ response in partially deficient HIF-1␣ mice after T/HS may be linked to the attenuation of villous and lung injury.…”

Section: Discussionmentioning

confidence: 99%

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury

Feinman

Deitch

Watkins

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

125

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mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 299: G833-G843, 2010. First published August 5, 2010 doi:10.1152/ajpgi.00065.2010.-Acute lung injury (ALI) and the development of the multiple organ dysfunction syndrome (MODS) are major causes of death in trauma patients. Gut inflammation and loss of gut barrier function as a consequence of splanchnic ischemia-reperfusion (I/R) have been implicated as the initial triggering events that contribute to the development of the systemic inflammatory response, ALI, and MODS. Since hypoxia-inducible factor (HIF-1) is a key regulator of the physiological and pathophysiological response to hypoxia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. Utilizing partially HIF-1␣-deficient mice in a global trauma hemorrhagic shock (T/HS) model, we found that HIF-1 activation was necessary for the development of gut injury and that the prevention of gut injury was associated with an abrogation of lung injury. Specifically, in vivo studies demonstrated that partial HIF-1␣ deficiency ameliorated T/HS-induced increases in intestinal permeability, bacterial translocation, and caspase-3 activation. Lastly, partial HIF-1␣ deficiency reduced TNF-␣, IL-1␤, cyclooxygenase-2, and inducible nitric oxide synthase levels in the ileal mucosa after T/HS whereas IL-1␤ mRNA levels were reduced in the lung after T/HS. This study indicates that prolonged intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. Consequently, these results provide unique information on the initiating events in trauma-hemorrhagic shock-induced ALI and MODS as well as potential therapeutic insights. hemorrhagic shock; inflammation; multiple organ dysfunction syndrome; acute lung injury IN PATIENTS SUSTAINING major trauma, the development of the systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction (MODS) is a major clinical problem resulting in 50 -80% of all deaths in surgical intensive care units. Since the pathophysiology of this syndrome remains incompletely understood and therapy remains largely supportive (16), studies focusing on the basic biology of traumainduced SIRS, organ injury/dysfunction, and MODS have been major areas of investigation. These mechanistic studies have generated several working hypotheses, one of which is the gut hypothesis of MODS. A key element in the gut hypothesis of MODS is that a splanchnic ischemia-reperfusion (I/R) insult leading to gut inflammation and loss of barrier function is the initial triggering event that turns the gut into the "motor" of MODS (19). However, the exact mechanisms by which gut I/R leads to intestinal injury and how an intestinal ischemic insult is transduced into a systemic inflammatory response remains incomplete. To date, the majority of the molecular and cellular studies investigating shock-induced gut injury and gut-induced MODS have focused pr...

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“…On the basis of recent studies showing that cytokines (46), bacteria (30,39), LPS (30,47), and nitric oxide (9) are capable of activating HIF-1 in numerous cell types, including enterocytes, it is possible that gut I/R-induced inflammatory mediators act in a positive feedback loop to sustain elevated HIF-1 levels, thereby, shifting the balance from HIF-1 being adaptive to maladaptive. It would also be of interest to deteremine whether HIF-2␣ manifests a proinflammatory role in our SMAO model using mice devoid of HIF-2␣ in the intestinal epithelium since HIF-2␣ has been recently implicated in myeloidand colonic-mediated inflammatory responses (24,32,49).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury

Kannan

Colorado

Reino

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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DZ, Semenza GL, Deitch EA, Feinman R. Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury. Am J Physiol Gastrointest Liver Physiol 300: G853-G861, 2011. First published December 23, 2010 doi:10.1152/ajpgi.00459.2010.-Gut injury and loss of normal intestinal barrier function are key elements in the paradigm of gutorigin systemic inflammatory response syndrome, acute lung injury, and multiple organ dysfunction syndrome (MODS). As hypoxiainducible factor (HIF-1) is a critical determinant of the physiological and pathophysiological response to hypoxia and ischemia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. Using partially HIF-1␣-deficient mice in an isolated superior mesenteric artery occlusion (SMAO) intestinal ischemia reperfusion (I/R) injury model (45 min SMAO followed by 3 h of reperfusion), we showed a direct relationship between HIF-1 activation and intestinal I/R injury. Specifically, partial HIF-1␣ deficiency attenuated SMAO-induced increases in intestinal permeability, lipid peroxidation, mucosal caspase-3 activity, and IL-1␤ mRNA levels. Furthermore, partial HIF-1␣ deficiency prevented the induction of ileal mucosal inducible nitric oxide synthase (iNOS) protein levels after SMAO and iNOS deficiency ameliorated SMAO-induced villus injury. Resistance to SMAO-induced gut injury was also associated with resistance to lung injury, as reflected by decreased levels of myeloperoxidase, IL-6 and IL-10 in the lungs of HIF-1␣ ϩ/Ϫ mice. In contrast, a short duration of SMAO (15 min) followed by 3 h of reperfusion neither induced mucosal HIF-1␣ protein levels nor caused significant gut and lung injury in wild-type or HIF-1␣ ϩ/Ϫ mice. This study indicates that intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. However, the duration and severity of the gut I/R insult dictate whether HIF-1 plays a gut-protective or deleterious role.inflammation; inducible nitric oxide synthase; mucosal injury MULTIPLE ORGAN DYSFUNCTION syndrome (MODS) is the major cause of morbidity and mortality in critically ill patients. A key paradigm in the development of the systemic inflammatory response syndrome (SIRS) and acute respiratory distress syndrome (ARDS) that culminates in multiple organ dysfunction syndrome (MODS) is loss of intestinal barrier function (10, 12). Intestinal ischemia reperfusion (I/R) injury occurs in different clinical settings, such as trauma, shock, burn, mesenteric artery occlusion, abdominal, cardiac bypass, and thoracic vascular surgery, as well as small intestinal transplantation.Because the gut acts as the "motor" of SIRS, ARDS, and MODS (6) and therapy for the critically ill patient remains largely supportive, studies identifying the underlying pathophysiological factors in the gut that initiate and propagate SIRS, ARDS, and MODS are of critical importance. To date, studies investigating the gut inflammatory/injurious response have primarily fo...

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LPS Increases Hepatic HIF-1α Protein and Expression of the HIF-1-Dependent Gene Aldolase A in Rats

Cited by 19 publications

References 25 publications

Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease

Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury

Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury

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