Modulation of Non‐Alcoholic Steatohepatitis by Pattern Recognition Receptors in Mice: The Role of Toll‐Like Receptors 2 and 4

Szabó, Gyöngyi; Velayudham, Arumugam; Romics, L; Mandrekar, Pranoti

doi:10.1097/01.alc.0000189287.83544.33

Cited by 125 publications

(111 citation statements)

References 28 publications

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…In fact, ob/ob and db/db mice have decreased intestinal resistance with enhanced LPS-induced pro-inflammatory and fibrogenic responses in hepatic stellate cells, which present higher mCD14 expression. Moreover, in the methionine-choline deficient diet-induced model of nonalcoholic steatohepatitis, TLR4-mediated liver injury and inflammatory cytokine induction are enhanced (Szabo et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Attenuation of the cardiovascular and metabolic complications of obesity in CD14 knockout mice

et al. 2008

View full text Add to dashboard Cite

Aims: Although toll-like receptors (TLR) are known to mediate the metabolic complications of obesity, the mechanisms underlying its activation remain largely unknown. The present study analyzed a model of dietinduced obesity in mice lacking the TLR4/TLR2 co-receptor CD14. Main methods: Six-week-old male mice lacking CD14 (n = 16) were allocated to either a control diet or a highfat high-simple carbohydrate diet (5.4 kcal/g; 35% fat; 35% sucrose), and compared with C57BL/6 (WT; n = 15) controls. After 12 weeks, body composition, basal sympathetic activity, non-invasive blood pressure and glucose tolerance were evaluated. Hepatic and adipose tissues were collected for mRNA quantification, histology and LPS incubation. Key findings: In both WT and CD14 knockout mice, obesity was accompanied by TLR2 and TLR4 upregulation. However, obese mice lacking CD14 presented decreased lipid and macrophage content in hepatic and adipose tissues, lower urinary levels of noradrenaline, decreased systolic blood pressure, reduced fasting plasma glucose and blunted glucose intolerance, compared with obese WT group. In the presence of exogenous sCD14, adipose tissue incubation with LPS-induced TLR2 and TNF-α upregulation in both WT and CD14 knockout obese mice. Significance: In our model of diet-induced obesity, mice lacking CD14 showed lower adiposity and hepatic steatosis, improved glucose homeostasis, blunted sympathetic overactivity and reduced blood pressure elevation. This was observed in the presence of preserved TLR4 and TLR2 gene expression, and intact TLR4 signaling pathways. These results suggest that CD14-mediated TLR activation might contribute to the cardiovascular and metabolic complications of obesity.

show abstract

Section: Discussionmentioning

confidence: 99%

Attenuation of the cardiovascular and metabolic complications of obesity in CD14 knockout mice

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Yet another option is that bacterial endotoxins in the portal circulation contribute to the pathogenesis of MCD-mediated hepatic inflammation. This is controversial, because mice with defects in Toll-like receptor 2 signaling have been reported to be even more susceptible to MCD-mediated liver disease than wild-type mice (34).…”

Section: Discussionmentioning

confidence: 99%

Polyunsaturated fat in the methionine-choline-deficient diet influences hepatic inflammation but not hepatocellular injury

Lee

Yan

et al. 2007

Journal of Lipid Research

View full text Add to dashboard Cite

Methionine-choline-deficient (MCD) diets that cause steatohepatitis in rodents are typically enriched in polyunsaturated fat. To determine whether the fat composition of the MCD formula influences the development of liver disease, we manufactured custom MCD formulas with fats ranging in PUFA content from 2% to 59% and tested them for their ability to induce steatohepatitis. All modifiedfat MCD formulas caused identical degrees of hepatic steatosis and resulted in a similar distribution of fat within individual hepatic lipid compartments. The fatty acid composition of hepatic lipids, however, reflected the fat composition of the diet. Mice fed a PUFA-rich MCD formula showed extensive hepatic lipid peroxidation, induction of proinflammatory genes, and histologic inflammation. When PUFAs were substituted with more saturated fats, lipid peroxidation, proinflammatory gene induction, and hepatic inflammation all declined significantly. Despite the close relationship between PUFAs and hepatic inflammation in mice fed MCD formulas, dietary fat had no impact on MCD-mediated damage to hepatocytes. Indeed, histologic apoptosis and serum alanine aminotransferase levels were comparable in all MCD-fed mice regardless of dietary fat content.Together, these results indicate that dietary PUFAs promote hepatic inflammation but not hepatotoxicity in the MCD model of liver disease. These findings emphasize that individual dietary nutrients can make specific contributions to steatohepatitis.-Lee, G. S., J.

show abstract

“…In comparison to wild-type mice, TLR2-deiciency animals are substantially protected from high-fat diet-induced adiposity, insulin resistance, hypercholesterolemia, and hepatic steatosis [39]. In contrast, increased hepatic inlammation and TNFmRN" expression were observed in TLR2-deiciency mice fed with MCDD [33,40]. The conlicting results of the role of TLR2 signaling in those studies could be due to diferent animal models used, diferent gut microbial ligands involved or compensation by other TLRs.…”

mentioning

confidence: 99%

“…Elevated plasma and portal LPS levels are evident in human and animals with N"FLD [2 , 29-32]. In methionine choline deicient diet MCDD)-induced mouse model of N"SH, liver injury and inlammatory cytokine production increased after challenge with LPS [33]. Rivera et al further demonstrated histological change typical of steatohepatitis extensive macrovesicular steatosis and necrosis), three-fold increase of portal blood endotoxin level, and enhanced TLR4 expression in wild-type mice fed with MCDD [31].…”

mentioning

confidence: 99%

Nonalcoholic Fatty Liver Disease in Children: Role of the Gut Microbiota

Li¹,

Yang²,

Gong³

et al. 2016

The Gut Microbiome - Implications for Human Disease

View full text Add to dashboard Cite

Nonalcoholic faty liver disease N"FLD) has emerged as the most common cause of liver disease among children and adolescents in industrialized countries due to increasing prevalence of obesity. It is generally recognized that both genetic and environmental risk factors contribute to the pathogenesis of N"FLD. Convincing evidences have shown that gut microbiota alteration is associated with N"FLD pathogenesis both in patients and animal models. "acterial overgrowth and increased intestinal permeability are evident in N"FLD patients and lead to increased delivery of gut-derived bacterial products, such as lipopolysaccharide and bacterial DN", to the liver through portal vein and then activation of toll-like receptors TLRs), mainly TLR4 and TLR9, and their downstream cytokines and chemokines, resulting in hepatic inlammation. Currently, the role of gut microbiota in the pathogenesis of N"FLD is still the focus of many active clinical/basic researches. Modulation of gut microbiota with probiotics or prebiotics has been targeted as a preventive or therapeutic strategy on this pathological condition. Their beneicial efects on the N"FLD have been demonstrated in animal models and limited human studies.

show abstract

Modulation of Non‐Alcoholic Steatohepatitis by Pattern Recognition Receptors in Mice: The Role of Toll‐Like Receptors 2 and 4

Cited by 125 publications

References 28 publications

Attenuation of the cardiovascular and metabolic complications of obesity in CD14 knockout mice

Attenuation of the cardiovascular and metabolic complications of obesity in CD14 knockout mice

Polyunsaturated fat in the methionine-choline-deficient diet influences hepatic inflammation but not hepatocellular injury

Nonalcoholic Fatty Liver Disease in Children: Role of the Gut Microbiota

Contact Info

Product

Resources

About