ChREBP regulates fructose-induced glucose production independently of insulin signaling.
Obese, insulin-resistant states are characterized by a paradoxical pathogenic condition in which the liver appears to be selectively insulin resistant. Specifically, insulin fails to suppress glucose production, yet successfully stimulates de novo lipogenesis. The mechanisms underlying this dysregulation remain controversial. Here, we hypothesized that carbohydrate-responsive element-binding protein (ChREBP), a transcriptional activator of glycolytic and lipogenic genes, plays a central role in this paradox. Administration of fructose increased hepatic hexose-phosphate levels, activated ChREBP, and caused glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis in mice. Activation of ChREBP was required for the increased expression of glycolytic and lipogenic genes as well as glucose-6-phosphatase (G6pc) that was associated with the effects of fructose administration. We found that fructose-induced G6PC activity is a major determinant of hepatic glucose production and reduces hepatic glucose-6-phosphate levels to complete a homeostatic loop. Moreover, fructose activated ChREBP and induced G6pc in the absence of Foxo1a, indicating that carbohydrate-induced activation of ChREBP and G6PC dominates over the suppressive effects of insulin to enhance glucose production. This ChREBP/G6PC signaling axis is conserved in humans. Together, these findings support a carbohydrate-mediated, ChREBP-driven mechanism that contributes to hepatic insulin resistance.
Mi-Sung
MS
Kim
Sarah A
SA
Krawczyk
Ludivine
L
Doridot
Alan J
AJ
Fowler
Jennifer X
JX
Wang
Sunia A
SA
Trauger
Hye-Lim
HL
Noh
Hee Joon
HJ
Kang
John K
JK
Meissen
Matthew
M
Blatnik
Jason K
JK
Kim
Michelle
M
Lai
Mark A
MA
Herman
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism; D005632:Fructose / Q000633:toxicity*; D005947:Glucose / Q000096:biosynthesis* / Q000235:genetics; D018149:Glucose Intolerance / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D007328:Insulin; C116385:MLXIPL protein, human; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D005632:Fructose; D005952:Glucose-6-Phosphatase; D005947:Glucose
J Biol Chem. 2008 Aug 29;283(35):24029-38
18591247
FASEB J. 1994 Apr 1;8(6):414-9
8168691
J Biol Chem. 2014 Jan 17;289(3):1313-28
24288132
Biochem J. 2012 Apr 1;443(1):111-23
22214556
Methods Mol Biol. 2009;560:221-38
19504253
Eur J Biochem. 1989 Jan 15;179(1):179-84
2917560
J Clin Invest. 2005 May;115(5):1343-51
15864352
Am J Clin Nutr. 2003 Jan;77(1):43-50
12499321
Cell Metab. 2008 Feb;7(2):95-6
18249166
Diabetes. 2013 Dec;62(12):4070-82
23990365
Br J Nutr. 2010 Oct;104(8):1139-47
20540820
Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1143-8
25564660
Am J Physiol Endocrinol Metab. 2006 Aug;291(2):E358-64
16705063
Anal Biochem. 2009 May 1;388(1):97-101
19454216
Diabetes. 1996 Nov;45(11):1594-604
8866566
Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3441-6
20133650
Biochim Biophys Acta. 2011 Aug;1812(8):995-1006
21453770
Anal Biochem. 1988 Aug 15;173(1):185-9
2847588
JAMA. 2002 Jan 16;287(3):356-9
11790215
Anal Chem. 2010 Jun 1;82(11):4403-12
20433152
J Biol Chem. 2004 Jul 30;279(31):32345-53
15166226
Cell Metab. 2016 Jun 14;23(6):1154-66
27238637
J Biol Chem. 2014 Jul 25;289(30):20462-9
24907277
Biochim Biophys Acta. 2008 May;1782(5):341-8
18346472
Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12121-6
19587243
J Lipid Res. 2011 Feb;52(2):189-206
21041806
Endocrinology. 2013 Jan;154(1):36-44
23161873
Mol Endocrinol. 2008 Jul;22(7):1658-72
18436566
Biochem Pharmacol. 2013 Feb 1;85(3):306-12
23022226
Clin Chem. 1988 Aug;34(8):1657
2841049
Circ Res. 2014 Jul 7;115(2):238-51
24874427
J Clin Invest. 2001 Nov;108(9):1359-67
11696581
Diabetes. 2013 Mar;62(3):837-44
23209190
J Med Chem. 2012 Feb 9;55(3):1318-33
22196621
Cell Metab. 2011 Jul 6;14(1):9-19
21723500
J Clin Invest. 2002 May;109(9):1125-31
11994399
J Clin Invest. 2012 Jun;122(6):2176-94
22546860
Nat Commun. 2013;4:1528
23443556
Cell. 2015 Feb 12;160(4):745-58
25662011
J Clin Invest. 2004 Dec;114(11):1666-75
15578099
J Clin Invest. 2009 May;119(5):1322-34
19381015
Nat Med. 2013 Aug;19(8):1054-60
23832089
Cell Metab. 2006 Aug;4(2):107-10
16890538
Diabetes Care. 2010 Nov;33(11):2477-83
20693348
J Clin Endocrinol Metab. 2015 Jun;100(6):2434-42
25825943
Biochem J. 2008 Aug 15;414(1):1-18
18651836
J Clin Invest. 2005 Mar;115(3):718-27
15711641
Biochem Biophys Res Commun. 2010 Jan 8;391(2):1166-9
20025850
Mol Cell. 2000 Jul;6(1):77-86
10949029
Proc Natl Acad Sci U S A. 2001 Nov 20;98 (24):13710-5
11698644
Proc Natl Acad Sci U S A. 2004 May 11;101(19):7281-6
15118080
Trends Endocrinol Metab. 2013 May;24(5):257-68
23597489
J Biol Chem. 1957 May;226(1):497-509
13428781
J Clin Invest. 2006 Feb;116(2):521-7
16453026
Nature. 2003 May 29;423(6939):550-5
12754525
Nat Genet. 2008 Feb;40(2):149-51
18193046
Lipids. 2016 Jan;51(1):95-104
26526060
J Biol Chem. 1998 Nov 20;273(47):31615-20
9813078
Cell Metab. 2007 Sep;6(3):208-16
17767907
Diabetes. 1988 Dec;37(12):1595-607
3056758
Hepatology. 2009 Jan;49(1):106-15
19053045
Am J Physiol. 1984 Oct;247(4 Pt 1):E505-12
6437238
J Clin Invest. 1995 May;95(5):2232-8
7738188
J Hepatol. 2012 Jan;56(1):199-209
21835137
Nature. 2012 Apr 19;484(7394):333-8
22466288
Diabetes. 2006 Aug;55(8):2159-70
16873678
Cell Metab. 2012 Jun 6;15(6):873-84
22682225
J Biol Chem. 2006 Sep 29;281(39):28721-30
16885160