Regulation of adiponectin receptor expression in human liver and a hepatocyte cell line

Shimizu, Akiko; Takamura, Toshinari; Matsuzawa, Naoto; Nakamura, Seiji; Nabemoto, Satoko; Takeshita, Yumie; Makino, Hírofumi; Kurita, Seiichiro; Sakurai, Masaru; Yokoyama, Masayoshi; Zen, Yoh; Sasaki, Motoko; Nakanuma, Yasuni; Kaneko, Shuichi

doi:10.1016/j.metabol.2007.06.013

Cited by 41 publications

(32 citation statements)

References 47 publications

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“…PPARγ is expressed at very low levels in the liver, and overexpression in the liver leads to hepatic steatosis with the expression of several adipogenic genes (26)(27)(28)(29). Conversely, PPARγ agonists have been used to treat nonalcoholic fatty liver (74), possibly by increasing expression of the receptor for adiponectin (75). Ethanol increases Pparg mRNA expression and expression of lipid synthetic enzymes ACL and FAS in mouse liver, and deletion or blockade of adenosine A 1 receptors decreased expression of these genes consistent with the results of the in vitro hepatocyte experiments.…”

Section: Figurementioning

confidence: 99%

Adenosine signaling contributes to ethanol-induced fatty liver in mice

Peng¹,

Borea²,

Wilder³

et al. 2009

J. Clin. Invest.

151

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Fatty liver is commonly associated with alcohol ingestion and abuse. While the molecular pathogenesis of these fatty changes is well understood, the biochemical and pharmacological mechanisms by which ethanol stimulates these molecular changes remain unknown. During ethanol metabolism, adenosine is generated by the enzyme ecto-5′-nucleotidase, and adenosine production and adenosine receptor activation are known to play critical roles in the development of hepatic fibrosis. We therefore investigated whether adenosine and its receptors play a role in the development of alcohol-induced fatty liver. WT mice fed ethanol on the LieberDeCarli diet developed hepatic steatosis, including increased hepatic triglyceride content, while mice lacking ecto-5′-nucleotidase or adenosine A 1 or A 2B receptors were protected from developing fatty liver. Similar protection was also seen in WT mice treated with either an adenosine A 1 or A 2B receptor antagonist. Steatotic livers demonstrated increased expression of genes involved in fatty acid synthesis, which was prevented by blockade of adenosine A 1 receptors, and decreased expression of genes involved in fatty acid metabolism, which was prevented by blockade of adenosine A 2B receptors. In vitro studies supported roles for adenosine A 1 receptors in promoting fatty acid synthesis and for A 2B receptors in decreasing fatty acid metabolism. These results indicate that adenosine generated by ethanol metabolism plays an important role in ethanol-induced hepatic steatosis via both A 1 and A 2B receptors and suggest that targeting adenosine receptors may be effective in the prevention of alcohol-induced fatty liver. IntroductionFatty liver is the most common and earliest response of the liver to heavy alcohol consumption and may develop into alcoholic hepatitis and fibrosis. Although fatty liver is a very common medical problem and the molecular events involved in the pathogenesis of fatty liver are well understood, the connection between ethanol ingestion and metabolism and the activation of the events involved in the development of hepatic steatosis is not well understood.

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Section: Figurementioning

confidence: 99%

Adenosine signaling contributes to ethanol-induced fatty liver in mice

Peng¹,

Borea²,

Wilder³

et al. 2009

J. Clin. Invest.

151

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“…In mice, AdipoR1 is abundantly expressed in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver (20). In humans, AdipoR1 and AdipoR2 have been reported to be expressed in adipocytes (21), skeletal muscle cells (22), vascular smooth muscle cells, macrophages (23), pancreatic β cells (24) and liver (25,26). The expression of adiponectin receptors has also been reported in various cancer tissues (27)(28)(29)(30)(31)(32), although the results are still controversial, and the role of the receptor expression in tumor tissues remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Adiponectin receptor 2 is negatively associated with lymph node metastasis of colorectal cancer

Hiyoshi¹

2012

Oncol Lett

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Abstract. Adiponectin is a hormone secreted by adipose tissue and has a variety of functions including the inhibition of tumor growth. The expression and function of the two major adiponectin receptors, AdipoR1 and AdipoR2, in malignant tissue have not been well characterized. In the present study, we evaluated the mRNA levels of AdipoR1 and AdipoR2 expression in 48 surgically resected colorectal cancer specimens, as well as normal colonic mucosa, by quantitative RT-PCR. The values obtained were standardized by β-actin mRNA, and the correlation between their relative expression levels and the clinicopathological characteristics of the patients was examined. The relative expression levels of AdipoR1 and AdipoR2 were significantly reduced in cancer tissue compared with normal tissue (AdipoR1: 0.97±0.39 vs. 1.37±0.41, P<0.0001; AdipoR2: 0.92±0.31 vs. 1.60±0.46, P<0.0001). AdipoR1 and AdipoR2 levels were further reduced in tumors with nodal metastases and the difference was statistically significant in the case of AdipoR2 (0.79±0.27 vs. 1.02±0.30, P=0.012). The results of this study demonstrated that the expression levels of adiponectin receptors are reduced in cancer specimens compared to normal tissue, indicating a downregulation in the course of the development and progression of colorectal cancer. Since adiponectin is abundantly present in the whole body and has inhibitory effects on cancer cells, this downregulation of the receptors may be an escape mechanism of malignant cells from the suppressive effects of adiponectin.

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“…In addition, hepatic expression of adiponectin receptor AdipoR2, but not AdipoR1, is downregulated in patients with NAFLD compared with those with a normal liver, independently of BMI [13]. In a nonmalignant human hepatocyte cell line, the THLE-5b cells, fatty acids downregulates, and a thiazolidinedione, pioglitazone, upregulates mRNA and protein of AdipoR2 [13]. These findings suggest that downregulation of AdipoR2 in the liver caused by steatosis, together with decreased serum levels of adiponectin, may play a role in the development of NAFLD.…”

Section: Pathology Of Fatty Liver Disease and Insulin Resistancementioning

confidence: 94%

“…The serum adiponectin levels are significantly lower in patients with NAFLD than in those with a normal liver, in a BMI-dependent manner. In addition, hepatic expression of adiponectin receptor AdipoR2, but not AdipoR1, is downregulated in patients with NAFLD compared with those with a normal liver, independently of BMI [13]. In a nonmalignant human hepatocyte cell line, the THLE-5b cells, fatty acids downregulates, and a thiazolidinedione, pioglitazone, upregulates mRNA and protein of AdipoR2 [13].…”

Section: Pathology Of Fatty Liver Disease and Insulin Resistancementioning

confidence: 99%

Fatty liver as a consequence and cause of insulin resistance: Lessons from type 2 diabetic liver

et al. 2012

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Abstract. Obesity is less common in the Asian population, but Asian people may be susceptible to obesity-associated metabolic dysregulation. Accumulating evidence suggests that insulin resistance is closely associated with ectopic fat accumulation in the liver. Whether this correlation is due to a causal relationship between the conditions has long been the subject of debate. Insulin resistance and type 2 diabetes affects liver pathology, typically leading to nonalcoholic fatty liver disease (NAFLD) by dynamically altering the hepatic genes involved in glucose and lipid metabolism. Conversely, how overnutrition induces hepatic insulin resistance has been studied intensively, and has been shown to involve excessive energy flux into mitochondria, toxic lipids, reactive oxygen species, and hepatokines. In this review, we focus on NAFLD both as a consequence and as a cause of insulin resistance through lessons learned from the liver of patients with type 2 diabetes.Key words: Fatty liver, Mitochondria, Reactive oxygen species, Hepatokine, Selenoprotein P TYPE 2 DIABETES is a multifactorial disease that involves a genetic predisposition and/or environmental factors leading to absolute and relative deficiencies in the actions of insulin. Recent studies have unraveled the humoral and nutritional factors, and a neuronal pathway that may govern inter-organ networks [1]. The disruption of inter-organ networks leads to insulin resistance, an underlying feature involved in the pathogenesis of type 2 diabetes and its related vascular complications. Specifically, the liver functions as a control tower to maintain human body energy homeostasis by sensing nutrient stimuli via portal vein and by producing a variety of nutrients and bioactive substances. Indeed, disruption of hepatic insulin signaling in liver-specific insulin receptor knockout (LIRKO) mice results in fasting and postprandial hyperglycemia and the subsequent development of peripheral (muscle) insulin resistance [2], whereas glucose homeostasis remains normal in mice of disrupted insulin signaling both in the skeletal muscle and adipose tissue [3]. These observations suggest that hepatic insulin resistance is the primary event leading to diabetes and the subsequent development of peripheral tissue insulin resistance.Over-nutrition is one of the major environmental factors that disrupt the inter-organ networks [1]. However, obesity is less common in Asian population. Nevertheless, Asian people may be suceptible to obesity-associated metabolic dysregulation. Accumulating evidence suggests that diabetes, obesity, and insulin resistance are closely associated with ectopic fat accumulation especially in the liver. Hepatic steatosis is often accompanied by hepatic insulin resistance. Whether this correlation is due to a causal relationship between the conditions has been the subject of considerable debate [4].In this review, we focus on nonalcoholic fatty liver disease (NAFLD) both as a consequence and as a cause of insulin resistance mainly through lessons learned from...

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Regulation of adiponectin receptor expression in human liver and a hepatocyte cell line

Cited by 41 publications

References 47 publications

Adenosine signaling contributes to ethanol-induced fatty liver in mice

Adenosine signaling contributes to ethanol-induced fatty liver in mice

Adiponectin receptor 2 is negatively associated with lymph node metastasis of colorectal cancer

Fatty liver as a consequence and cause of insulin resistance: Lessons from type 2 diabetic liver

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