iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: http://pubmed.ncbi.nlm.nih.gov/28591572/
Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans - PubMed Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Jun 6;19(10):1997-2004.
doi: 10.1016/j.celrep.2017.05.035.

Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans

Kasper W Ter Horst  1 , Pim W Gilijamse  1 , Ruth I Versteeg  1 , Mariette T Ackermans  2 , Aart J Nederveen  3 , Susanne E la Fleur  4 , Johannes A Romijn  5 , Max Nieuwdorp  6 , Dongyan Zhang  7 , Varman T Samuel  8 , Daniel F Vatner  8 , Kitt F Petersen  8 , Gerald I Shulman  9 , Mireille J Serlie  10
Affiliations

Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans

Kasper W Ter Horst et al. Cell Rep. .

Abstract

Hepatic lipid accumulation has been implicated in the development of insulin resistance, but translational evidence in humans is limited. We investigated the relationship between liver fat and tissue-specific insulin sensitivity in 133 obese subjects. Although the presence of hepatic steatosis in obese subjects was associated with hepatic, adipose tissue, and peripheral insulin resistance, we found that intrahepatic triglycerides were not strictly sufficient or essential for hepatic insulin resistance. Thus, to examine the molecular mechanisms that link hepatic steatosis to hepatic insulin resistance, we comprehensively analyzed liver biopsies from a subset of 29 subjects. Here, hepatic cytosolic diacylglycerol content, but not hepatic ceramide content, was increased in subjects with hepatic insulin resistance. Moreover, cytosolic diacylglycerols were strongly associated with hepatic PKCε activation, as reflected by PKCε translocation to the plasma membrane. These results demonstrate the relevance of hepatic diacylglycerol-induced PKCε activation in the pathogenesis of NAFLD-associated hepatic insulin resistance in humans.

Keywords: NAFLD; diacylglycerol; glucose clamp; hepatic glucose production; hepatic steatosis; human; insulin resistance; obesity; protein kinase Cε.

PubMed Disclaimer

Figures

None
Graphical abstract
Figure 1
Figure 1
The Presence of Hepatic Steatosis, but Not Its Extent, Is Associated with Insulin Resistance in Obese Humans (A) The basal rate of EGP was assessed after an overnight fast. (B) Hepatic insulin sensitivity is expressed as the insulin-mediated suppression of basal EGP. (C) Adipose tissue insulin sensitivity is expressed as the insulin-mediated suppression of circulating FA. (D) Peripheral insulin sensitivity is expressed as the insulin-stimulated Rd of glucose. Data are mean ± SEM (n = 125–133). ∗∗∗p ≤ 0.001.
Figure 2
Figure 2
Relationships between IHTG Content and Tissue-Specific Measurements of Insulin Sensitivity in Obese Subjects Were Best Described by Nonlinear Models (A) Hepatic insulin sensitivity. (B) Adipose tissue insulin sensitivity. (C) Peripheral insulin sensitivity. Lines are best fit and 95% CI (n = 125–133).
Figure 3
Figure 3
Hepatic Insulin Resistance Was Strongly Associated with Elevated DAG Content in the Cytosolic Fraction and PKCε Translocation (A) Hepatic ceramide content in obese subjects with normal hepatic insulin sensitivity or hepatic insulin resistance. (B) Total hepatic DAG content. (C) Hepatic DAG content in cytosolic fraction. (D) Hepatic DAG content in membrane fraction. (E) Individual DAG species in hepatic cytosol. Note the segmented y axis. (F) Representative bands show PKCε translocation from cytosol to membrane. (G) Translocation of PKCε from cytosol (c) to membrane (m) as an index of activation. Data are mean ± SEM (n = 18–29). ∗p < 0.05. ∗∗p < 0.01. ∗∗∗p = 0.001.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ackermans M.T., Pereira Arias A.M., Bisschop P.H., Endert E., Sauerwein H.P., Romijn J.A. The quantification of gluconeogenesis in healthy men by (2)H2O and [2-(13)C]glycerol yields different results: Rates of gluconeogenesis in healthy men measured with (2)H2O are higher than those measured with [2-(13)C]glycerol. J. Clin. Endocrinol. Metab. 2001;86:2220–2226. - PubMed
    1. Amaro A., Fabbrini E., Kars M., Yue P., Schechtman K., Schonfeld G., Klein S. Dissociation between intrahepatic triglyceride content and insulin resistance in familial hypobetalipoproteinemia. Gastroenterology. 2010;139:149–153. - PMC - PubMed
    1. Benhamed F., Denechaud P.D., Lemoine M., Robichon C., Moldes M., Bertrand-Michel J., Ratziu V., Serfaty L., Housset C., Capeau J. The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans. J. Clin. Invest. 2012;122:2176–2194. - PMC - PubMed
    1. Brown J.M., Betters J.L., Lord C., Ma Y., Han X., Yang K., Alger H.M., Melchior J., Sawyer J., Shah R. CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance. J. Lipid Res. 2010;51:3306–3315. - PMC - PubMed
    1. Buettner R., Ottinger I., Schölmerich J., Bollheimer L.C. Preserved direct hepatic insulin action in rats with diet-induced hepatic steatosis. Am. J. Physiol. Endocrinol. Metab. 2004;286:E828–E833. - PubMed

Publication types