Adiponectin and its receptors in non-alcoholic steatohepatitis

Abstract

Background: Adiponectin, an adipocyte derived polypeptide, has been shown to alleviate steatosis and inflammation in mice with non-alcoholic fatty liver disease. Aim: In the present study, we wished to define liver expression of adiponectin and its receptors in morbidly obese patients undergoing bariatric surgery. Patients with non-alcoholic steatohepatitis (NASH) or simple steatosis were investigated to test whether dysregulation of this system might be involved in these disorders. Patients and methods: Liver mRNA expression of adiponectin and its recently cloned receptors RI and RII (adipoRI and adipoRII) were analysed by fluorescence based real time polymerase chain reaction in 13 patients with NASH and nine with simple steatosis. Adiponectin and adipoRII protein expression were assessed by immunohistochemistry in a subgroup of patients. Results: Adiponectin and adipoRII mRNA expression were significantly reduced in liver biopsies of patients with NASH compared with simple steatosis while no difference was found in adipoRI mRNA expression. In NASH, adipoRII mRNA expression was negatively correlated with serum aspartate aminotransferase levels, serum alanine aminotransferase levels, and grade of fibrosis. Liver adiponectin protein expression was mainly found in endothelial cells of portal vessels and liver sinusoids whereas adipoRII expression was seen in hepatocytes only. Adiponectin and adipoRII staining were lower in biopsies of subjects with NASH compared with simple steatosis. Conclusion: Reduced hepatic expression of adiponectin and adipoRII might be of pathophysiological relevance in non-alcoholic fatty liver diseases. N on-alcoholic steatohepatitis (NASH) is frequently associated with abdominal obesity, hypertension, and diabetes. Insulin resistance has been implicated as a key mechanism in the pathogenesis of NASH. Numerous substances, mainly released by adipocytes, are thought to contribute to peripheral insulin resistance. These include proinflammatory cytokines such as interleukin (IL)-6 and tumour necrosis factor a (TNF-a) as well as leptin, resistin, and also acrp30/adiponectin/adipoQ. 1 2 Adiponectin is an antidiabetic and antiatherogenic acting polypeptide that is strongly correlated with systemic insulin sensitivity in humans.1 3 4 Adiponectin increases fatty acid beta oxidation in muscle, 5 improves postabsorptive insulin mediated suppression of hepatic glucose output by enhancing hepatic insulin action, 6 and decreases lipid accumulation in macrophages. 7 Beyond its metabolic effects, adiponectin also has direct anti-inflammatory effects. 8Xu et al reported that adiponectin administration alleviates non-alcoholic fatty liver disease in mice. In detail, administration of adiponectin improved hepatomegaly and steatosis, attenuated inflammation, and elevated levels of serum alanine aminotransferase in ob/ob mice. Recently, cloning of adiponectin receptors I and II (adipoRI and adipoRII) was reported.10 While in mice adipoRI is abundantly expressed in skeletal muscle, adipoRII is predominantly e...

Metabolic profiles in patients with chronic hepatitis C: a case–control study

“…Our findings showed the existence of a close link between HCV infection and metabolic abnormalities. We found that HCV infection was positively correlated with serum adiponectin level, which was different from previously reports on subjects with non-alcoholic steatohepatitis (NASH) [20,33].…”

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

“…On the other hand, IVA337 increased circulating adiponectin, a canonical PPARγ target that contributes to decreasing inflammation and improving insulin resistance in the liver; the adverse effect of PPARγ activation in the adipose tissue is adipogenesis and fat mass gain. In patients, adiponectin inversely correlates with steatosis and steatohepatitis 45. Together, this supports the conclusion that the effects of IVA337 on insulin sensitivity, body weight gain, and other metabolic disorders induced by the HF/HS diet or HF diet in foz/foz mice result from the concomitant activation of the three PPAR isoforms and that a pan‐PPAR activation could potentially deliver a superior improvement of NASH‐associated metabolic disorders compared to individual PPAR agonists.…”

Regulation of adiponectin release and demonstration of adiponectin mRNA as well as release by the non-fat cells of human omental adipose tissue

“…28 Approximately, the same rate of release was seen by cut pieces of adipose tissue that did not contain enough lipid to float. 28 The view that the expression of adiponectin mRNA is restricted to mature adipocytes is clearly untenable in view of the present findings and the recent reports that adiponectin is synthesized and secreted by human osteoblasts, 10 human cardiomyocytes, 11 murine skeletal muscle, 12 human skeletal muscle and placenta, 13 human liver biopsies, 14 human placental synctiotrophoblasts, 15 as well as human fetal tissues of both mesodermal and ectodermal origin. 16 The present data using omental adipose tissue explants confirm the prior reports by Matsuzawa's laboratory that adiponectin release is reduced by obesity 4 as well as diabetes.…”

“…7,8 Adiponectin was originally described as an adipocytespecific protein. [1][2][3] However, more recently adiponectin mRNA and secretion have been demonstrated in boneforming cells, 9,10 cardiomyocytes, 11 skeletal muscle, 12,13 human liver, 14 human placental syncytiotrophoblasts 15 and human fetal tissues of mesodermic and ectodermal origin. 16 It is unclear whether tissues other than adipose tissue contribute to circulating levels of adiponectin that are some 40-fold higher than those of leptin in obese subjects.…”