Strong Association between Serum Hepatocyte Growth Factor and Metabolic Syndrome

Hiratsuka, Akiko; Adachi, Hisashi; Fujiura, Yoshihisa; Yamagishi, Sho‐ichi; Hirai, Yuji; Enomoto, Masaru; Satoh, Akira; Hino, Asuka; Furuki, Kumiko; Imaizumi, Tsutomu

doi:10.1210/jc.2004-1588

Cited by 61 publications

(59 citation statements)

References 18 publications

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“…HGF release into the culture medium was quantitated by ELISA. *P ϭ 0.02. recent large study of Japanese men and women, serum HGF was strongly associated with metabolic syndrome independently from liver function (10). Taken together, these studies suggest that elevated serum HGF in obesity may contribute to the development of cardiovascular disease.…”

Section: Discussionmentioning

confidence: 60%

“…More recently, the role of HGF in cardiovascular disease has been reemphasized by the fact that high circulating levels of HGF in patients with coronary artery disease predict a greater long-term risk of atherothrombotic events following percutaneous coronary revascularization (29). Furthermore, Hiratsuka et al (10) found that serum HGF levels are strongly associated with components of the metabolic syndrome in individuals free of liver and kidney disease. Taken together, these observations and others implicate HGF in the development of cardiovascular disease and cancer.…”

mentioning

confidence: 99%

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Adipose tissue production of hepatocyte growth factor contributes to elevated serum HGF in obesity

Bell¹,

Ward²,

Degawa-Yamauchi³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

102

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Serum HGF is elevated in obese individuals. This study examined the contribution of excess adipose tissue to increased circulating HGF levels in obesity. Serum HGF was measured by ELISA before and after weight loss due to bariatric surgery or a 24-h fast. At 6.1 ± 0.1 mo following surgery, BMI (50.6 ± 1.6 vs. 35.1 ± 1.3 kg/m2; P < 0.0001) and serum HGF were significantly decreased (1,164 ± 116 vs. 529 ± 39 pg/ml, P < 0.001). A 24-h fast did not change serum HGF, but serum leptin was significantly reduced (67.7 ± 7.1 vs. 50.3 ± 8.3 ng/ml, P = 0.02). HGF secretion in vitro from adipocytes of obese (BMI 40.3 ± 2.8 kg/m2) subjects was significantly greater (80.9 ± 10.4 vs. 21.5 ± 4.0 pg/105 cells, P = 0.008) than release from adipocytes of lean (BMI 23.3 ± 1.4 kg/m2) subjects. HGF mRNA levels determined by real-time RT-PCR were not different in adipocytes from lean (BMI 24.0 ± 0.8 kg/m2) and obese (45.7 ± 3.0 kg/m2) subjects, but serum HGF was significantly elevated in the obese individuals studied (787 ± 61 vs. 489 ± 49 pg/ml, P = 0.001). TNF-α (24 h treatment) significantly increased HGF release from subcutaneous adipocytes 23.6 ± 8.3% over control ( P = 0.02). These data suggest that elevated serum HGF in obesity is in part attributable to excess adipose tissue and that this effect can be reversed by reducing adipose tissue mass through weight loss. Increased HGF secretion from adipocytes of obese subjects may be due to posttranscriptional events possibly related to adipocyte size and stimulation by elevated TNF-α in the adipose tissue of obese individuals.

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Section: Discussionmentioning

confidence: 60%

mentioning

confidence: 99%

Adipose tissue production of hepatocyte growth factor contributes to elevated serum HGF in obesity

Bell¹,

Ward²,

Degawa-Yamauchi³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

102

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“…On the other hand weight loss after gastroplasty has been shown to be associated with a reduction of HGF plasma levels in obese patients (12,14). A strong association between elevated serum HGF and metabolic syndrome has also been reported (15).…”

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confidence: 98%

Hepatocyte Growth Factor Induces Glucose Uptake in 3T3-L1 Adipocytes through A Gab1/Phosphatidylinositol 3-Kinase/Glut4 Pathway

Bertola

Bonnafous

Cormont

et al. 2007

Journal of Biological Chemistry

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Adipose tissue is a source of hepatocyte growth factor (HGF), and circulating HGF levels have been associated with elevated body mass index in human. However, the effects of HGF on adipocyte functions have not yet been investigated. We show here that in 3T3-L1 adipocytes HGF stimulates the phosphatidylinositol (PI) 3-kinase-dependent protein kinase B (PKB) activity, AS160 phosphorylation, Glut4 translocation, and consequently, glucose uptake. The initial steps involved in HGF-and insulininduced glucose uptake are different. HGF enhanced the tyrosine phosphorylation of Gab1, leading to the recruitment of the p85-regulated subunit of PI 3-kinase, whereas p85 was exclusively recruited by IRS1 in response to insulin. In adipocytes rendered insulin-resistant by a long-lasting tumor necrosis factor ␣ treatment, the protein level of Gab1 was strongly decreased, and HGF-stimulated PKB activation and glucose uptake were also altered. Moreover, treatment of 3T3-L1 adipocytes with thiazolidinedione, an anti-diabetic drug, enhanced the expression of both HGF and its receptor. These data provide the first evidence that in vitro HGF promotes glucose uptake through a Gab1/PI 3-kinase/PKB/AS160 pathway which was altered in tumor necrosis factor ␣-treated adipocytes.

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“…Furthermore, HGF levels have been reported to be elevated in obese patients and raised with body mass index (6 -10). On the other hand, weight loss after gastroplasty has been shown to be associated with a reduction of HGF plasma levels in obese patients (6). A strong association between elevated serum HGF and metabolic syndrome has also been reported (6 -10).…”

mentioning

confidence: 99%

Hepatocyte Growth Factor Family Negatively Regulates Hepatic Gluconeogenesis via Induction of Orphan Nuclear Receptor Small Heterodimer Partner in Primary Hepatocytes

Chanda

Song

et al. 2009

Journal of Biological Chemistry

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Hepatic gluconeogenesis is tightly balanced by opposing stimulatory (glucagon) and inhibitory (insulin) signaling pathways. Hepatocyte growth factor (HGF) is a pleiotropic growth factor that mediates diverse biological processes. In this study, we investigated the effect of HGF and its family member, macrophage-stimulating factor (MSP), on hepatic gluconeogenesis in primary hepatocytes. HGF and MSP significantly repressed expression of the key hepatic gluconeogenic enzyme genes, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (Glc-6-Pase) and reduced glucose production. HGF and MSP activated small heterodimer partner (SHP) gene promoter and induced SHP mRNA and protein levels, and the effect of HGF and MSP on SHP gene expression was demonstrated to be mediated via activation of the AMP-activated protein kinase (AMPK) signaling pathway. We demonstrated that upstream stimulatory factor-1 (USF-1) specifically mediated HGF effect on SHP gene expression, and inhibition of USF-1 by dominant negative USF-1 significantly abrogated HGF-mediated activation of the SHP promoter. Elucidation of the mechanism showed that USF-1 bound to E-box-1 in the SHP promoter, and HGF increased USF-1 DNA binding on the SHP promoter via AMPK and DNA-dependent protein kinase-mediated pathways. Adenoviral overexpression of USF-1 significantly repressed PEPCK and Glc-6-Pase gene expression and reduced glucose production. Knockdown of endogenous SHP expression significantly reversed this effect. Finally, knockdown of SHP or inhibition of AMPK signaling reversed the ability of HGF to suppress hepatocyte nuclear factor 4␣-mediated up-regulation of PEPCK and Glc-6-Pase gene expression along with the HGFand MSP-mediated suppression of gluconeogenesis. Overall, our results suggest a novel signaling pathway through HGF/ AMPK/USF-1/SHP to inhibit hepatic gluconeogenesis.

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Strong Association between Serum Hepatocyte Growth Factor and Metabolic Syndrome

Cited by 61 publications

References 18 publications

Adipose tissue production of hepatocyte growth factor contributes to elevated serum HGF in obesity

Adipose tissue production of hepatocyte growth factor contributes to elevated serum HGF in obesity

Hepatocyte Growth Factor Induces Glucose Uptake in 3T3-L1 Adipocytes through A Gab1/Phosphatidylinositol 3-Kinase/Glut4 Pathway

Hepatocyte Growth Factor Family Negatively Regulates Hepatic Gluconeogenesis via Induction of Orphan Nuclear Receptor Small Heterodimer Partner in Primary Hepatocytes

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