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1.
Figure 5

Figure 5. Reduced de novo lipogenesis in Alb-Cre;Lrh1fl/fl mice. . From: LRH-1-dependent glucose sensing determines intermediary metabolism in liver.

(A) Hepatic lipogenic gene expression and (B) de novo synthesis of hepatic palmitate, stearate, and oleate in fed, fasted, and refed Lrh1fl/fl mice (white bars) and Alb-Cre;Lrh1fl/fl mice (black bars) (n = 7–9 per genotype). Data represent mean ± SEM. *P < 0.05 versus Lrh1fl/fl.

Maaike H. Oosterveer, et al. J Clin Invest. 2012 August 1;122(8):2817-2826.
2.
Figure 4

Figure 4. Delayed glycogen synthesis and reduced glycolysis in Alb-Cre;Lrh1fl/fl mice. . From: LRH-1-dependent glucose sensing determines intermediary metabolism in liver.

(A) Representative glycogen stainings during oral glucose tolerance test (n = 3–8 per genotype). Scale bar: 200 μm. (B) Quantification of hepatic glycogen content in Lrh1fl/fl mice (white boxes) and Alb-Cre;Lrh1fl/fl mice (black boxes) during oral glucose tolerance test. (C) Hepatic glycogen content in fed, 24-hour–fasted, or 6-hour–refed Lrh1fl/fl mice (white bars) and Alb-Cre;Lrh1fl/fl mice (black bars) (n = 7 per genotype). (D) Extracellular acidification rates (ECARs) in Lrh1fl/fl (white boxes) and Alb-Cre;Lrh1fl/fl (black boxes) primary hepatocytes (n = 5–6 per genotype). Data represent mean ± SEM. *P < 0.05 versus Lrh1fl/fl.

Maaike H. Oosterveer, et al. J Clin Invest. 2012 August 1;122(8):2817-2826.
3.
Figure 1

Figure 1. Reduced hepatic glucokinase and glycogen synthase fluxes in Alb-Cre;Lrh1fl/fl mice. . From: LRH-1-dependent glucose sensing determines intermediary metabolism in liver.

(A) Schematic representation of the model used for mass isotopomer distribution analysis. GP, glycogen phosphorylase; GS, glycogen synthase; G6Pase, glucose-6-phosphatase. (BD) Glucose fluxes in Lrh1fl/fl mice (white bars) and Alb-Cre;Lrh1fl/fl mice (black bars) under normoglycemic (NG) and hyperglycemic (HG) conditions. (B) Glucokinase and (C) glucose-6-phosphatase flux and (D) glucose balance. (EG) Glycogen fluxes in Alb-Cre;Lrh1fl/fl and Lrh1fl/fl mice under normoglycemic and hyperglycemic conditions. (E) Glycogen synthase and (F) glycogen phosphorylase flux and (G) glycogen balance. Data represent mean ± SEM for n = 5–9 per genotype. *P < 0.05 Alb-Cre;Lrh1fl/fl versus Lrh1fl/fl; #P < 0.05 hyperglycemic versus normoglycemic.

Maaike H. Oosterveer, et al. J Clin Invest. 2012 August 1;122(8):2817-2826.
4.
Figure 2

Figure 2. Reduced glucokinase expression in Alb-Cre;Lrh1fl/fl mice. . From: LRH-1-dependent glucose sensing determines intermediary metabolism in liver.

(A) Blood glucose and (B) plasma insulin concentrations (n = 10 per genotype) and (C and D) hepatic mRNA levels of Lrh1, Shp, Gck, and Hk1 during an oral glucose tolerance test (n = 4–8 per genotype) in Lrh1fl/fl mice (white boxes) and Alb-Cre;Lrh1fl/fl mice (black boxes). (E and F) Hepatic mRNA levels in fed, 24-hour–fasted or 6-hour–refed Lrh1fl/fl mice (white bars) and Alb-Cre;Lrh1fl/fl mice (black bars) (n = 7–9 per genotype). (G) LRH-1 transcriptional activity in HeLa cells transfected with a heterologous (4x LRH-1 response element–Luc [4xLRE-Luc]) or an endogenous LRH-1 reporter driven by the Shp promoter (SHP-Luc). Luciferase activity was determined in the absence (empty; white bars) or presence (LRH-1; black bars) of LRH-1 after exposure to 5 or 25 mM glucose for 24 hours. Data are expressed as relative light units (RLUs) compared with empty reporter (pGL3). Data represent mean ± SEM. *P < 0.05 versus Lrh1fl/fl or versus empty vector (pCMX).

Maaike H. Oosterveer, et al. J Clin Invest. 2012 August 1;122(8):2817-2826.
5.
Figure 6

Figure 6. Impaired GCK activity in Alb-Cre;Lrh1fl/fl mice reduces ChREBP expression and activity. . From: LRH-1-dependent glucose sensing determines intermediary metabolism in liver.

(A) Hepatic Chrebp, Pklr, Srebp-1c, and G6pd1 expression in fed, 24-hour–fasted, or 6-hour–refed Lrh1fl/fl mice (white bars) and Alb-Cre;Lrh1fl/fl mice (black bars) (n = 7–9 per genotype). (B) Nuclear ChREBP protein expression in 24-hour–fasted and 6-hour–refed Lrh1fl/fl and Alb-Cre;Lrh1fl/fl mice. (C) Hepatic G6P content in fasted and refed Lrh1fl/fl mice (white bars) and Alb-Cre;Lrh1fl/fl mice (black bars) (n = 6–7 per genotype). (D) Hepatic Chrebp and Pklr expression in Alb-Cre;Lrh1fl/fl mice 5 weeks after in vivo transduction of the liver using AAV8-SHP virus (gray bars) in comparison with that in Lrh1fl/fl mice (white bars) and Alb-Cre;Lrh1fl/fl mice (black bars) (n = 4–5 per group). (E) Luciferase activities in HeLa cells transfected with Chrebp (ChREBP-Luc) or SHP (SHP-Luc) promoter (black bars) constructs in the absence (empty; white bars) or presence (LRH-1; black bars) of LRH-1. Data are expressed as relative light units and normalized to empty reporter (pGL3). (F) Hepatic mRNA levels in Alb-Cre;Lrh1fl/fl mice 5 weeks after in vivo transduction of the liver using 2 different titers of AAV8-GCK virus (low, 1011 particles per mouse [light gray bars], and high, 1012 particles per mouse [dark gray bars]) in comparison with those in Lrh1fl/fl mice (white bars) and Alb-Cre;Lrh1fl/fl mice (black bars) (n = 4–5 per group). Data represent mean ± SEM. *P < 0.05 versus Lrh1fl/fl or versus empty vector (pCMX); #P < 0.05 versus Alb-Cre;Lrh1fl/fl.

Maaike H. Oosterveer, et al. J Clin Invest. 2012 August 1;122(8):2817-2826.
6.
Figure 3

Figure 3. Gck is a direct transcriptional target of LRH-1. . From: LRH-1-dependent glucose sensing determines intermediary metabolism in liver.

(A) Hepatic mRNA levels in Alb-Cre;Lrh1fl/fl mice 5 weeks after in vivo transduction of the liver using AAV8-SHP virus (gray bars) in comparison with those in Lrh1fl/fl mice (white bars) and Alb-Cre;Lrh1fl/fl mice (black bars) (n = 4–5 per group). (B) Hepatic GCK protein expression in refed Lrh1fl/fl and Alb-Cre;Lrh1fl/fl mice. (C and D) Expression levels of LRH-1 and its targets in (C) wild-type primary hepatocytes and (D) Hepa 1.6 mouse hepatoma cells transduced with AdGFP (white bars) or AdLRH-1 (black bars) viruses (n = 3 per condition). (E) 2-deoxyglucose (2-DG) uptake and 2-deoxyglucose-6-phosphate (2-DG6P) production in Hepa 1.6 cells transduced with AdGFP (white bars) or AdLRH-1 (black bars) viruses (n = 6 per condition). (F) Schematic presentation of the 6 putative LRH-1 response elements in the mouse Gck promoter. (G) Assessment of LRH-1 recruitment to these sites, as depicted in F, determined by ChIP analysis using genomic DNA from livers of Lrh1fl/fl and Alb-Cre;Lrh1fl/fl mice. (H) Luciferase activities in HeLa cells transfected with empty luciferase reporter (pGL3; white bar) or long and short Gck promoter constructs (black bars). Data are expressed as fold induction in luciferase activity upon LRH-1 cotransfection. Data represent mean ± SEM. *P < 0.05 versus Lrh1fl/fl, versus GFP, or versus empty reporter (pGL3); #P < 0.05 versus Alb-Cre;Lrh1fl/fl.

Maaike H. Oosterveer, et al. J Clin Invest. 2012 August 1;122(8):2817-2826.

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