Toll-like receptor-2 deficiency enhances non-alcoholic steatohepatitis

BMC Gastroenterology

Research Article

LaTausha Gaskin¹  Patrick Adegboyega¹  Kevin Pruitt¹  Monique Allman¹  Jia Pang¹  Kristen Brady¹  Chantal A Rivera² 

[1] Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA;Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA;Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA, USA;

关键词: Wild Type Mouse;    Saturated Fatty Acid;    NASH Pathogenesis;    Fibrogenic Potential;    Moment Statistical Test;   

DOI  :  10.1186/1471-230X-10-52

 received in 2009-10-25, accepted in 2010-05-28,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundPreviously we reported that mice deficient in toll-like receptor 4 (TLR-4) signalling were protected from diet-induced non-alcoholic steatohepatitis (NASH). Another member of the toll-like receptor family, TLR-2, has been shown to play a role in lipid trafficking via uptake of diacylated lipoproteins. However, a role for TLR-2 in NASH has not been elucidated. The objectives of the current study were to examine the influence of dietary fat quality and TLR-2 on NASH pathogenesis.MethodsSteatohepatitis was induced in male Db, C57BL/6 and TLR-2-/- mice by feeding an L-amino acid-defined diet that was deficient in methionine and choline (MCDD). Mice fed the base diet supplemented with methionine and choline (control diet; CD) were used as controls. To determine the role of fat quality, MCDD was enriched with polyunsaturated corn oil (PUFA) or coconut oil that is comprised mostly of saturated fat (SAFA); the total amount of each fat was 112.9 g/kg of diet. After 8 weeks of feeding CD or MCDD, hepatic steatosis, inflammation and necrosis were evaluated in histological sections. Total RNA was extracted from frozen liver samples and mRNA expression of TNFα, collagen α1, IL-10, peroxisome proliferator-activated receptor-γ (PPAR-γ), TLR-4, and CD14, was analyzed via real-time PCR. Protein levels of TLR-2 were analyzed by western blot.ResultsPanlobular macrovessicular steatosis and diffuse leukocyte infiltration were noted in PUFA-fed Db mice. Histological scores demonstrated significantly less steatosis, inflammation and necrosis in SAFA-fed mice of all mouse strains. However, compared to wild type mice, hepatocellular damage was notably more severe in TLR-2-/- mice. Consistent with histological findings, mRNA expression of TNFα was elevated by approximately 3-fold in TLR-2-/- mice; PPAR-γ expression was blunted in this strain compared to wild type. Expression of the matrix protein collagen αI was also significantly higher in TLR-2-/- mice, indicating a pro-fibrogenic state. Sensitivity to steatohepatitis due to dietary fat or TLR-2 deficiency correlated significantly with alterations in the expression of TLR-4 as well as the co-receptor CD-14.ConclusionsOur findings suggest that dietary saturated fat plays a protective role against MCDD-induced steatohepatitis, whereas TLR-2 deficiency exacerbated NASH. The mechanism underlying the response to dietary fat and TLR-2 likely involves altered signalling via the TLR-4 pathway.

【 授权许可】

CC BY   
© Rivera et al; licensee BioMed Central Ltd. 2010