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Omaha, NE, United States

Aziz-Seible R.S.,Creighton University | Casey C.A.,University of Nebraska Medical Center | Casey C.A.,The Liver Study Unit
World Journal of Gastroenterology | Year: 2011

Fibronectins are adhesive glycoproteins that can befound in tissue matrices and circulating in various fluidsof the body. The variable composition of fibronectinmolecules facilitates a diversity of interactions with cellsurface receptors that suggest a role for these proteinsbeyond the structural considerations of the extracellularmatrix. These interactions implicate fibronectin inthe regulation of mechanisms that also determine cellbehavior and activity. The two major forms, plasmafibronectin (pFn) and cellular fibronectin (cFn), existas balanced amounts under normal physiological conditions.However, during injury and/or disease, tissueand circulating levels of cFn become disproportionatelyelevated. The accumulating cFn, in addition to being aconsequence of prolonged tissue damage, may in factstimulate cellular events that promote further damage.In this review, we summarize what is known regardingsuch interactions between fibronectin and cells that mayinfluence the biological response to injury. We elaborateon the effects of cFn in the liver, specifically under acondition of chronic alcohol-induced injury. Studies haverevealed that chronic alcohol consumption stimulatesexcess production of cFn by sinusoidal endothelial cellsand hepatic stellate cells while impairing its clearance byother cell types resulting in the build up of this glycoproteinthroughout the liver and its consequent increasedavailability to influence cellular activity that could promotethe development of alcoholic liver disease. Wedescribe recent findings by our laboratory that support aplausible role for cFn in the promotion of liver injury undera condition of chronic alcohol abuse and the implicationsof cFn stimulation on the pathogenesis of alcoholicliver disease. These findings suggest an effect of cFn inregulating cell behavior in the alcohol-injured liver thatis worth further characterizing not only to gain a morecomprehensive understanding of the role this reactiveglycoprotein plays in the progression of injury but alsofor the insight further studies could provide towardsthe development of novel therapies for alcoholic liverdisease. © 2011 Baishideng.

Rasineni K.,University of Nebraska Medical Center | Rasineni K.,The Liver Study Unit | Penrice D.D.,University of Nebraska Medical Center | Penrice D.D.,The Liver Study Unit | And 9 more authors.
BMC Gastroenterology | Year: 2016

Background: Non-alcoholic and alcoholic fatty liver disease (NAFLD and AFLD, respectively) are major health problems, as patients with either condition can progress to hepatitis, fibrosis, and cirrhosis. Although histologically similar, key differences likely exist in these two models. For example, altered content of several vesicle trafficking proteins have been identified in AFLD, but their content in NAFLD is unknown. In this study, we compared select parameters in NAFLD and AFLD in a rat model. Methods: We fed either Lieber- DeCarli liquid control or alcohol-containing (35 % as calories) diet (AFLD model) or lean or high-fat (12 or 60 % derived from fat, respectively) pellets (NAFLD model) for 8-10 weeks, n = 8 in each model. Serum, hepatocytes and liver tissue were analyzed. Liver injury markers were measured in serum, triglyceride content and endocytosis (binding and internalization of 125I- asialoorosomucoid) was measured in isolated hepatocytes, and content of selected trafficking proteins (Rab3D, Rab7 and Rab18) were determined in whole liver tissue. Results: Although liver injury markers and triglyceride content were similar in both models, binding and internalization of 125I- asialoorosomucoid was significantly impaired in the hepatocytes from AFLD, but not NAFLD, animals. In addition, protein content of the asialoglycoprotein receptor (ASGPR) and three trafficking proteins, Rab3D, Rab7and Rab18, were significantly decreased after alcohol, but not high-fat feeding. Levels of protein carbonylation, amount of glutathione stores, and lipid peroxidation were similar irrespective of the insult to the livers that resulted in fatty liver. Conclusion: Impairments in protein trafficking in AFLD are likely a direct result of alcohol administration, and not a function of fatty liver. © 2016 Rasineni et al.

Rasineni K.,The Liver Study Unit | Rasineni K.,University of Nebraska Medical Center | Mcvicker B.L.,The Liver Study Unit | Mcvicker B.L.,University of Nebraska Medical Center | And 5 more authors.
Alcoholism: Clinical and Experimental Research | Year: 2014

Background: Alcoholic liver disease is manifested by the presence of fatty liver, primarily due to accumulation of hepatocellular lipid droplets (LDs). The presence of membrane-trafficking proteins (e.g., Rab GTPases) with LDs indicates that LDs may be involved in trafficking pathways known to be altered in ethanol (EtOH) damaged hepatocytes. As these Rab GTPases are crucial regulators of protein trafficking, we examined the effect EtOH administration has on hepatic Rab protein content and association with LDs. Methods: Male Wistar rats were pair-fed Lieber-DeCarli diets for 5 to 8 weeks. Whole liver and isolated LD fractions were analyzed. Identification of LDs and associated Rab proteins was performed in frozen liver or paraffin-embedded sections followed by immunohistochemical analysis. Results: Lipid accumulation was characterized by larger LD vacuoles and increased total triglyceride content in EtOH-fed rats. Rabs 1, 2, 3d, 5, 7, and 18 were analyzed in postnuclear supernatant (PNS) as well as LDs. All of the Rabs were found in the PNS, and Rabs 1, 2, 5, and 7 did not show alcohol-altered content, while Rab 3d content was reduced by over 80%, and Rab 18 also showed EtOH-induced reduction in content. Rab 3d was not found to associate with LDs, while all other Rabs were found in the LD fractions, and several showed an EtOH-related decrease (Rabs 2, 5, 7, 18). Immunohistochemical analysis revealed the enhanced content of a LD-associated protein, perilipin 2 (PLIN2) that was paralleled with an associated decrease of Rab 18 in EtOH-fed rat sections. Conclusions: Chronic EtOH feeding was associated with increased PLIN2 and altered Rab GTPase content in enriched LD fractions. Although mechanisms driving these changes are not established, further studies on intracellular protein trafficking and LD biology after alcohol administration will likely contribute to our understanding of fatty liver disease. © 2013 by the Research Society on Alcoholism.

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