Diverse regulation of NF-kappaB and peroxisome proliferator-activated receptors in murine nonalcoholic fatty liver
Authors
Romics, LaszloKodys, Karen
Dolganiuc, Angela
Graham, Lucia
Velayudham, Arumugam
Mandrekar, Pranoti
Szabo, Gyongyi
UMass Chan Affiliations
Department of Medicine, Rheumatology DivisionDepartment of Medicine, Division of Gastroenterology
Document Type
Journal ArticlePublication Date
2004-09-16Keywords
AnimalsCell Nucleus
Cytokines
Ethanol
Fatty Liver
Female
Inflammation Mediators
Interleukin-6
Leptin
Lipopolysaccharides
Liver
Mice
NF-kappa B
Obesity
Receptors, Cytoplasmic and Nuclear
Transcription Factors
Tumor Necrosis Factor-alpha
Gastroenterology
Hepatology
Metadata
Show full item recordAbstract
Fatty liver is highly sensitive to inflammatory activation. Peroxisome proliferator-activated receptors (PPAR) have anti-inflammatory effects and regulate lipid metabolism in the fatty liver. We hypothesized that fatty liver leads to endotoxin sensitivity through an imbalance between pro- and anti-inflammatory signals. Leptin-deficient, ob/ob mice and their lean littermates were challenged with single or double insults and pro- and anti-inflammatory pathways were tested on cytokine production and activation of nuclear regulatory factors NF-kappaB and peroxisome proliferator receptor element (PPRE). Ob/ob mice produced significantly higher serum tumor necrosis factor alpha (TNF-alpha) and interleukin (IL) 6 and showed increased hepatic NF-kappaB activation compared to lean littermates after stimulation with a single dose of lipopolysaccharide (LPS) or alcohol. In ob/ob mice, double insults with alcohol and LPS augmented proinflammatory responses mediated by increased degradation of inhibitory kappaB (IkappaB)-alpha and IkappaB-beta and preferential induction of the p65/p50 NF-kappaB heterodimer. In lean mice, in contrast, acute alcohol attenuated LPS-induced TNF-alpha, IL-6 production, and NF-kappaB activation through reduced IkappaB-alpha degradation and induction of p50/p50 homodimers. PPRE binding was increased in fatty but not in lean livers after alcohol or LPS stimulation. However, cotreatment with alcohol and LPS reduced both PPRE binding and nuclear levels of PPAR-alpha in fatty livers but increased those in lean livers. In conclusion, our results show opposite PPRE and NF-kappaB activation in fatty and lean livers. PPAR activation may represent an anti-inflammatory mechanism that fails in the fatty liver on increased proinflammatory pressure. Thus, an imbalance between PPAR-mediated anti-inflammatory and NF-kappaB-mediated proinflammatory signals may contribute to increased inflammation in the fatty liver.Source
Hepatology. 2004 Aug;40(2):376-85. Link to article on publisher's siteDOI
10.1002/hep.20304Permanent Link to this Item
http://hdl.handle.net/20.500.14038/31113PubMed ID
15368442Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1002/hep.20304