Esmaili, Saeed, George, Jacob, and Hebbard, Lionel (2012) The role of adiponectin and cholesterol in NAFLD progression. Journal of Gastroenterology and Hepatology, 27 (s4). p. 4.

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Abstract

Background Lipid toxicity and infl ammation are important components in the transition of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Factors such as reduced adiponectin have been associated with hepatic steatosis and inflammation, and have also been shown to influence sphingolipid metabolism. Recent data suggests that the level of free cholesterol is associated with the severity of liver disease. In this study we examined the association of adiponectin and cholesterol to NAFLD progression.

Aims To investigate the role of adiponectin and cholesterol in NAFLD progression.

Methods Male C57BL/6 and Adiponectin KO (ADN) mice were fed normal chow (NC) or a high cholesterol (HC) diet containing 2% cholesterol and 0.5% cholate for 12 weeks. At 4 weeks, Glucose Tolerance Tests (GTT), Insulin Tolerance Tests (ITT), and Pyruvate Challenge Tests (PCT) were performed. At experiment end, serum and hepatic cholesterol, and free fatty acids were measured. Hepatic sphingolipid levels were determined using LC/MS. Liver tissues were examined by haematoxylin and eosin (H&E), sirius red, TUNEL and CD68 immunostaining. For in vitro analyses, rat kupffer and stellate cells were isolated and treated with acetylated LDL. qPCR and western blots of tissues and cells were undertaken.

Results When fed the high cholesterol diet, both genotypes had similar increases in average liver/total body weight ratio and reduced fat pad weight. Wild-type mice had greater insulin sensitivity (p < 0.05). Biochemistry and histology showed that KO mice fed the HC (ADN-HC) diet had elevated hepatic total (148 vs. 92 mg/dl), and free cholesterol (99 vs. 80 mg/dl), greater fibrosis, more apoptosis and 2-fold more macro- phages than WT fed HC (WT-HC). ADN-HC livers had increased gene expression for TNFα (10-fold), IL-1β (1.4-fold), CCL19 (6.0-fold,), CD3ε (2.0-fold), LTα (2.0-fold), CD40L (9.0-fold) and TLR4 (1.4 fold, all statistically significant), and through western analyses activation of the non-canonical NF-κB pathway, compared to WT-HC. LC/MS analysis of the liver showed a 2-fold increase in ceramide, a 2-fold decrease in sphingo- sine-1-P and a 1.5 fold increase in glucosylceramide levels in ADN-HC compared to WT-HC mice (all p < 0.01). In preliminary in vitro experiments we find that treatment of HSCs and Kupffer cells with acetylated LDL and LPS leads to increased expression of TLR4 and p100 processing to p52.

Conclusion These data show that adiponectin null mice fed a high cholesterol diet develop robust hepatic inflammation, and have increased TLR4 expression and canonical and non-canonical NF-κB activation. We find that ceramide and sphingosine levels are altered and additionally that glucosylceramide is more elevated in ADN-HC fed mice than WT-HC. Importantly, this unique inflammatory and sphingolipid signature offers potential therapeutic avenues to limit NAFLD progression.

Item ID:	86252
Item Type:	Article (Abstract)
ISSN:	1440-1746
Copyright Information:	© 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.
Date Deposited:	22 Jul 2025 00:48
FoR Codes:	32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320209 Gastroenterology and hepatology @ 100%
SEO Codes:	20 HEALTH > 2001 Clinical health > 200101 Diagnosis of human diseases and conditions @ 100%
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