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Expression of NALPs in adipose and the fibrotic progression of non-alcoholic fatty liver disease in obese subjects.

Mehta R, Neupane A, Wang L, Goodman Z, Baranova A, Younossi ZM - BMC Gastroenterol (2014)

Bottom Line: In portal fibrosis, the levels of mRNA encoding anti-inflammatory NALP6 were upregulated.The expression levels of all NALPs were significantly co-correlated.Circulating IL-18 levels were associated with increased liver injury markers AST and ALT and portal fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Betty and Guy Beatty Obesity and Liver Program, Inova Health System, Falls Church, VA, USA. mehta.rohini@gmail.com.

ABSTRACT

Background: Visceral obesity is often accompanied by non-alcoholic fatty liver disease (NAFLD). Activation of NACHT, LRR and PYD domains-containing proteins (NALPs) may contribute to the release of pro-inflammatory cytokines by adipose and the obesity-associated progression of NAFLD to non-alcoholic steatohepatitis (NASH).

Methods: We analyzed visceral adipose expression of various NALPs and its downstream effectors caspase-1, ASC (Apoptosis-associated speck-like protein containing a CARD), IL-18 (Interleukin-18) and IL-1β (Interleukin- 1Beta) in obese subjects (BMI ≥ 35) with biopsy proven NAFLD.

Results: In adipose samples collected from NASH and pericellular fibrosis patients cohorts, expression levels of NALPs and IL-1β were lower than that in non-NASH patients. In portal fibrosis, the levels of mRNA encoding anti-inflammatory NALP6 were upregulated. The expression levels of all NALPs were significantly co-correlated. Circulating IL-18 levels were associated with increased liver injury markers AST and ALT and portal fibrosis.

Conclusion: Our observations point at a possible shift in inflammation and fibrotic response from adipose tissue to liver and a possible negative feedback regulation of tissue inflammation that may instigate NAFLD severity.

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Significantly altered gene expression in presence of NASH vs non-NASH NAFLD.
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Fig2: Significantly altered gene expression in presence of NASH vs non-NASH NAFLD.

Mentions: The observed downregulation of adipose-specific production of IL1B mRNA in patients with pericellular fibrosis (Table 2 and Figure 1) as well as NASH (Table 2 and Figure 2) also supports this hypothesis. The downregulation at expression level is also supported by the lack of detectable IL1B protein levels in circulation (Assay Range: 0.125 - 8 pg/mL). Unlike the production of most inflammatory cytokines, the production of biologically active IL-1β is dependent on transcription, translation, maturation and secretion mechanisms, all of which are tightly regulated in tissue-specific manner. This may be attributed to tissue specific roles of IL1B. Animal studies showed that hepatic IL-1β protein and mRNA levels to be increased in various diet-induced NASH models in mice [28], while adipose specific IL1B deficiency in mice increase susceptibility to obesity [28,37]. In another recent study, the authors demonstrate in animal models that IL-1β supports ectopic fat accumulation in hepatocytes and adipose-tissue macrophages, contributing to impaired fat-liver crosstalk in nutritional obesity [38]. While the translation of animal studies to humans is difficult, the discrepancy in observed expression levels of IL1B in obesity associated NASH and pericellular fibrosis maybe attributed to the extremely high BMI of the cohort being examined (BMI ≥ 35). This along with the observed negative correlation of IL1B mRNA levels with BMI (r = −0.317; p = 0.04) indicates an ongoing negative feedback loop between adipose specific IL1B expression and an accumulation of VAT.Figure 1


Expression of NALPs in adipose and the fibrotic progression of non-alcoholic fatty liver disease in obese subjects.

Mehta R, Neupane A, Wang L, Goodman Z, Baranova A, Younossi ZM - BMC Gastroenterol (2014)

Significantly altered gene expression in presence of NASH vs non-NASH NAFLD.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4279907&req=5

Fig2: Significantly altered gene expression in presence of NASH vs non-NASH NAFLD.
Mentions: The observed downregulation of adipose-specific production of IL1B mRNA in patients with pericellular fibrosis (Table 2 and Figure 1) as well as NASH (Table 2 and Figure 2) also supports this hypothesis. The downregulation at expression level is also supported by the lack of detectable IL1B protein levels in circulation (Assay Range: 0.125 - 8 pg/mL). Unlike the production of most inflammatory cytokines, the production of biologically active IL-1β is dependent on transcription, translation, maturation and secretion mechanisms, all of which are tightly regulated in tissue-specific manner. This may be attributed to tissue specific roles of IL1B. Animal studies showed that hepatic IL-1β protein and mRNA levels to be increased in various diet-induced NASH models in mice [28], while adipose specific IL1B deficiency in mice increase susceptibility to obesity [28,37]. In another recent study, the authors demonstrate in animal models that IL-1β supports ectopic fat accumulation in hepatocytes and adipose-tissue macrophages, contributing to impaired fat-liver crosstalk in nutritional obesity [38]. While the translation of animal studies to humans is difficult, the discrepancy in observed expression levels of IL1B in obesity associated NASH and pericellular fibrosis maybe attributed to the extremely high BMI of the cohort being examined (BMI ≥ 35). This along with the observed negative correlation of IL1B mRNA levels with BMI (r = −0.317; p = 0.04) indicates an ongoing negative feedback loop between adipose specific IL1B expression and an accumulation of VAT.Figure 1

Bottom Line: In portal fibrosis, the levels of mRNA encoding anti-inflammatory NALP6 were upregulated.The expression levels of all NALPs were significantly co-correlated.Circulating IL-18 levels were associated with increased liver injury markers AST and ALT and portal fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Betty and Guy Beatty Obesity and Liver Program, Inova Health System, Falls Church, VA, USA. mehta.rohini@gmail.com.

ABSTRACT

Background: Visceral obesity is often accompanied by non-alcoholic fatty liver disease (NAFLD). Activation of NACHT, LRR and PYD domains-containing proteins (NALPs) may contribute to the release of pro-inflammatory cytokines by adipose and the obesity-associated progression of NAFLD to non-alcoholic steatohepatitis (NASH).

Methods: We analyzed visceral adipose expression of various NALPs and its downstream effectors caspase-1, ASC (Apoptosis-associated speck-like protein containing a CARD), IL-18 (Interleukin-18) and IL-1β (Interleukin- 1Beta) in obese subjects (BMI ≥ 35) with biopsy proven NAFLD.

Results: In adipose samples collected from NASH and pericellular fibrosis patients cohorts, expression levels of NALPs and IL-1β were lower than that in non-NASH patients. In portal fibrosis, the levels of mRNA encoding anti-inflammatory NALP6 were upregulated. The expression levels of all NALPs were significantly co-correlated. Circulating IL-18 levels were associated with increased liver injury markers AST and ALT and portal fibrosis.

Conclusion: Our observations point at a possible shift in inflammation and fibrotic response from adipose tissue to liver and a possible negative feedback regulation of tissue inflammation that may instigate NAFLD severity.

Show MeSH
Related in: MedlinePlus