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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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Related in: MedlinePlus

Significantly altered targets in presence of portal fibrosis vs absence of portal fibrosis. A.) NALP6 gene expression; B.) Circulating IL18 levels.
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Fig3: Significantly altered targets in presence of portal fibrosis vs absence of portal fibrosis. A.) NALP6 gene expression; B.) Circulating IL18 levels.

Mentions: Further support to the hypothesis centering on ongoing negative feedback loop operating between adipose tissue and liver in morbidly obese individuals with severe NAFLD, is provided by result of the comparison in another cohort. In cohort of subjects with portal fibrosis compared to those without portal fibrosis, adipose specific NALP6 mRNA (Table 2 and Figure 3) and circulating IL18 (Table 2 and Figure 3) protein were upregulated with hepatic portal fibrosis, while adipose specific IL18 mRNA was not significantly different in the same cohort. This is interesting, since NALP6 has been shown to have an anti-inflammatory role by downregulating NF-κB signaling subsequent to TLR activation [3]. Conspicuously, whilst circulating IL-18 protein was upregulated in portal fibrosis (Table 2 and Figure 3), this was not accompanied with an upregulation of adipose specific IL18 mRNA. Additionally, circulating IL-18 was found to be positively correlated with BMI (r = 0.41; p = 0.012). This is in agreement with previous studies [39-43]. Notably, circulating IL-18 levels are also associated with increased liver injury markers [44]: AST (r = 0.33; p = 0.04) and ALT (r = 0.41; p = 0.01) levels respectively as seen in previous reports [43]. Since IL-18 is more widely expressed, this may indicate additional sources of circulating IL-18 protein such as from the gut [28] or the liver [45], playing a role in the inflammation and hepatic injury progression. Thus, IL-18 might contribute to the development of liver disease, albeit the origin of IL-18 may not be solely from adipose.Figure 3


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 targets in presence of portal fibrosis vs absence of portal fibrosis. A.) NALP6 gene expression; B.) Circulating IL18 levels.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: Significantly altered targets in presence of portal fibrosis vs absence of portal fibrosis. A.) NALP6 gene expression; B.) Circulating IL18 levels.
Mentions: Further support to the hypothesis centering on ongoing negative feedback loop operating between adipose tissue and liver in morbidly obese individuals with severe NAFLD, is provided by result of the comparison in another cohort. In cohort of subjects with portal fibrosis compared to those without portal fibrosis, adipose specific NALP6 mRNA (Table 2 and Figure 3) and circulating IL18 (Table 2 and Figure 3) protein were upregulated with hepatic portal fibrosis, while adipose specific IL18 mRNA was not significantly different in the same cohort. This is interesting, since NALP6 has been shown to have an anti-inflammatory role by downregulating NF-κB signaling subsequent to TLR activation [3]. Conspicuously, whilst circulating IL-18 protein was upregulated in portal fibrosis (Table 2 and Figure 3), this was not accompanied with an upregulation of adipose specific IL18 mRNA. Additionally, circulating IL-18 was found to be positively correlated with BMI (r = 0.41; p = 0.012). This is in agreement with previous studies [39-43]. Notably, circulating IL-18 levels are also associated with increased liver injury markers [44]: AST (r = 0.33; p = 0.04) and ALT (r = 0.41; p = 0.01) levels respectively as seen in previous reports [43]. Since IL-18 is more widely expressed, this may indicate additional sources of circulating IL-18 protein such as from the gut [28] or the liver [45], playing a role in the inflammation and hepatic injury progression. Thus, IL-18 might contribute to the development of liver disease, albeit the origin of IL-18 may not be solely from adipose.Figure 3

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