human liver biopsies
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Endocrinology ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 2820-2830 ◽  
Author(s):  
Rafael Simó ◽  
Cristina Saez-Lopez ◽  
Albert Lecube ◽  
Cristina Hernandez ◽  
Jose Manuel Fort ◽  
...  

Epidemiological studies have shown that plasma SHBG levels correlate with plasma adiponectin levels, both in men and women. There are no reports describing any molecular mechanism by which adiponectin regulates hepatic SHBG production. The aim of the present study is to explore whether adiponectin regulates SHBG production by increasing HNF-4α levels through reducing hepatic lipid content. For this purpose, in vitro studies using human HepG2 cells, as well as human liver biopsies, were performed. Our results show that adiponectin treatment increased SHBG production via AMPK activation in HepG2 cells. Adiponectin treatment decreased the mRNA and protein levels of enzymes related to hepatic lipogenesis (ACC) and increased those related to fatty acid oxidation (ACOX and CPTI). These adiponectin-induced changes in hepatic enzymes resulted in a reduction of total TG and FFA and an increase of HNF-4α. When HNF-4α expression was silenced by using siRNA, adiponectin-induced SHBG overexpression was blocked. Furthermore, adiponectin-induced upregulation of SHBG production via HNF-4α overexpression was abrogated by the inhibition of fatty acid oxidation or by the induction of lipogenesis with a 30mM glucose treatment in HepG2 cells. Finally, adiponectin levels correlated positively and significantly with both HNF-4α and SHBG mRNA levels in human liver biopsies. Our results suggest for the first time that adiponectin increases SHBG production by activating AMPK, which reduces hepatic lipid content and increases HNF-4α levels.


2011 ◽  
Vol 96 (7) ◽  
pp. E1126-E1130 ◽  
Author(s):  
Andreas Peter ◽  
Norbert Stefan ◽  
Alexander Cegan ◽  
Mareike Walenta ◽  
Silvia Wagner ◽  
...  

Abstract Background/Aims: Glucokinase (GCK) phosphorylates glucose to form glucose 6-phosphate and thereby regulates hepatic glucose disposal and activates hepatic lipogenesis. Hepatic GCK activity is regulated on the level of GCK mRNA expression and by the inhibitory glucokinase regulatory protein. In this study, we aimed to investigate the relation between GCK mRNA expression and markers of lipogenesis as well as liver fat content in human liver biopsies. Additionally, we investigated whether genetic variation in the liver specific GCK promoter determines liver fat content in humans. Methods: Hepatic mRNA expression and liver triglyceride content was analyzed in 50 human liver biopsies. In a second cohort of 330 individuals, liver fat was precisely measured by 1H magnetic resonance spectroscopy. Results: Hepatic GCK mRNA expression is associated with triglyceride content in human liver biopsies (r = 0.50, P = 0.0002). Furthermore, hepatic GCK mRNA expression is associated with lipogenic gene expression (fatty acid synthase, r = 0.49, P = 0.0003; acetyl-coenzyme A carboxylase-α, r = 0.44, P = 0.0015, and acetyl-coenzyme A carboxylase-β, r = 0.48, P = 0.0004) and the de novo lipogenesis index (r = 0.36, P = 0.01). In support of these findings, the single-nucleotide polymorphism rs2041547 in the liver-specific GCK promoter is associated with liver fat content in prediabetic individuals (P = 0.047). Conclusions: In this study, we demonstrate for the first time that GCK mRNA expression is associated with markers of de novo lipogenesis and liver triglyceride content in humans. This suggests that increased GCK activity may induce fatty liver and its metabolic and hepatic consequences in humans. Thus, the widely used approach to nonspecifically activate β-cell and hepatic GCK to treat diabetes mellitus is therefore questionable and may cause serious side effects.


Author(s):  
Per Christoffersen ◽  
Otto Braendstrup ◽  
Erik Juhl ◽  
Hemming Poulsen

2009 ◽  
Vol 185 (1-6) ◽  
pp. 9-12 ◽  
Author(s):  
E. Kemp ◽  
T. Laursen ◽  
O. Munck ◽  
T. Steen Olsen ◽  
N. Tygstrup

2008 ◽  
Vol 4 (2) ◽  
pp. 96-103 ◽  
Author(s):  
Viviana Falcon ◽  
Ivon Menendez ◽  
Nelson Acosta-Riv ◽  
Mineko Shibayama ◽  
Marlia-C de la Rosa ◽  
...  

Hepatology ◽  
2007 ◽  
Vol 46 (3) ◽  
pp. 649-657 ◽  
Author(s):  
Deborah L. Diamond ◽  
Jon M. Jacobs ◽  
Bryan Paeper ◽  
Sean C. Proll ◽  
Marina A. Gritsenko ◽  
...  

2005 ◽  
Vol 11 (S02) ◽  
Author(s):  
Y Pan ◽  
A Brown ◽  
R Brydson ◽  
A Warley ◽  
A Li ◽  
...  

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