Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Jun 15;169(7):1263-1275.e14.
doi: 10.1016/j.cell.2017.05.031.

Metabolic Adaptation Establishes Disease Tolerance to Sepsis

Affiliations
Free PMC article

Metabolic Adaptation Establishes Disease Tolerance to Sepsis

Sebastian Weis et al. Cell. .
Free PMC article

Abstract

Sepsis is an often lethal syndrome resulting from maladaptive immune and metabolic responses to infection, compromising host homeostasis. Disease tolerance is a defense strategy against infection that preserves host homeostasis without exerting a direct negative impact on pathogens. Here, we demonstrate that induction of the iron-sequestering ferritin H chain (FTH) in response to polymicrobial infections is critical to establish disease tolerance to sepsis. The protective effect of FTH is exerted via a mechanism that counters iron-driven oxidative inhibition of the liver glucose-6-phosphatase (G6Pase), and in doing so, sustains endogenous glucose production via liver gluconeogenesis. This is required to prevent the development of hypoglycemia that otherwise compromises disease tolerance to sepsis. FTH overexpression or ferritin administration establish disease tolerance therapeutically. In conclusion, disease tolerance to sepsis relies on a crosstalk between adaptive responses controlling iron and glucose metabolism, required to maintain blood glucose within a physiologic range compatible with host survival.

Keywords: disease tolerance; ferritin; gluconeogenesis; glucose-6-phosphatase; heme; infection; inflammation; iron; metabolism; sepsis.

Figures

None
Figure 1
Figure 1
FTH Establishes Disease Tolerance to Sepsis (A) FTH western blot from C57BL/6 mice liver extracts before (Control; Ctr) or 12 hr after a severe CLP. Representative western blot from one out of three mice per genotype. (B) Densitometry of FTH protein expression normalized to β-actin. Data pooled from three mice per genotype. (C) Representative immunostaining of liver FTH (green), DNA (blue), and F4/80+ Kupffer cells (red) before (Control; Ctr) or 12 hr after a severe CLP. (D) FTH western blot in liver extracts from Fthlox/lox and Mx1CreFthΔ/Δ mice before (Control; Ctr) and 48 hr after CLP. Representative of four mice per genotype. (E) Survival of Fthlox/lox (n = 20) and Mx1CreFthΔ/Δ (n = 17) mice subjected to CLP, pooled from four independent experiments. (F) Aerobic (Ae) and anaerobic (An) bacterial colony forming units (CFU), 48 hr after CLP. Data pooled from three independent experiments. (G) Survival after CLP in bone marrow chimeric mice expressing Fth in all tissues (Fth+/+Fth+/+, n = 14), in parenchyma only (FthΔ/ΔFth+/+, n = 14), or in bone marrow-derived cells only (Fth+/+FthΔ/Δ, n = 8). Data from three independent experiments with similar trend. (H) Survival of control Fthlox/lox mice (n = 35), AlbCreFthΔ/Δ (n = 12), LysMCreFthΔ/Δ (n = 24), and AlbCreLysMCreFthΔ/Δ (n = 12) mice lacking FTH expression in hepatocytes, myeloid cells, or hepatocytes and myeloid cells, respectively. Data pooled from ten independent experiments. (I and J) Clinical severity score (CSS) (Gonnert et al., 2011) (I) and survival of Fthlox/lox (n = 6) and Mx1CreFthΔ/Δ (n = 4) mice subjected to PCI (J). Data for CSS is from one independent experiment and survival is from two independent experiments. (K) CFU for aerobic (Ae) and anaerobic (An) bacteria 24 hr after PCI in two independent experiments. Red bars in (F) and (K) are mean values and dotted circles are individual mice. PC, peritoneal cavity. p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001. See also Figures S1, S2, and S3.
Figure S1
Figure S1
FTH Establishes Disease Tolerance to Sepsis, Related to Figure 1 (a) Representative FTH immunostaining in the liver of C57BL/6 mice before (Control) and 12 hr after severe CLP. Red: F4/80+ Kupffer cells; Green: FTH, Blue: DNA. (b) Control staining with secondary antibodies only. (c) Quantification of Fth mRNA by qRT-PCR before (Control; Ctr.) and 12 hr after CLP. Data are shown as mean ± SD of 3 mice per group. (d) Percentage of circulating CD45.1+ versus CD45.2+ leukocytes in control (Fth+/+Fth+/+), (Fth+/+FthΔ/Δ) and (FthΔ/ΔFth+/+) bone marrow chimeras. (e) Percentage of CD19+ B cells, TCRβ+ T cells, Gr1+CD11bhigh PMN cells and CD11b+ (monocyte/macrophages and PMN cells) in the same mice as in (d). Data in (d) and (e) is shown as mean ± SD of 4-6 mice per group, pooled from 2-3 representative experiments. (f) Fth mRNA expression quantified by qRT-PCR in circulating leukocytes and expressed as % relative to (B6→B6) controls. Data shown as mean ± SD of 3-4 mice per group, pooled from 2-3 representative experiments. p < 0.05.
Figure S2
Figure S2
FTH Does Not Modulate Cytokine Levels or Tissue Damage, Related to Figure 1 (a) Cytokine levels in plasma 24 hr after CLP. Mean ± SD (n = 4 per genotype). (b) Serological markers before (Control; Ctrl) and 48 hr after CLP. Mean ± SD, n = 3-5 mice per genotype, pooled from 3 independent experiments. (c) H&E stained paraffin sections representative of at least three Fthlox/lox and Mx1CreFthΔ/Δ mice untreated (Control) and 48 hr after CLP. B: bronchus; CV: central vein; G: glomerulus. Magnification 400x.
Figure S3
Figure S3
FTH Does Not Modulate Cardiovascular Function, Related to Figure 1 (a) H&E stained paraffin section of hearts from Fthlox/lox and Mx1CreFthΔ/Δ mice before and 48 hr after CLP. Images are representative of at least 3 mice per genotype per experimental conditions. Magnifications are 100 (top) and 400x. (b) Cardiac pressure-volume (PV) loop analysis of Fthlox/lox and Mx1CreFthΔ/Δ mice, 48 hr after CLP. Load-dependent, i.e. Heart rate (HR) end-systolic pressure (ESP), cardiac output (CO), relaxation (Tau-Glantz), pressure volume area (PVA) and mean arterial pressure (MAP) and load-independent, i.e. slope of end-systolic pressure volume Relationship (ESPVR) and maximum of generated energy (Emax) parameters are shown as mean ± SD from n = 3-6 mice per group pooled from 4 independent experiments. NS: non-significant. (c) Vascular leakage monitored by quantification of Evans Blue accumulation in parenchyma organs, before and 48 hr after CLP. Data are shown as mean ± SD from n = 5 mice per group, pooled from 3 independent experiments. NS: non-significant.
Figure 2
Figure 2
FTH Regulates Glucose Metabolism in Response to Polymicrobial Infection (A–C) Relative weight (A), temperature (B), and blood glucose levels (C) in Fthlox/lox (n = 13) and Mx1CreFthΔ/Δ (n = 15) mice subjected to CLP. Mean ± SEM from five independent experiments. (D) Blood glucose levels in Mx1CreFthΔ/Δ mice subjected to CLP and receiving glucose (n = 15) (gavage; 2 mg/kg body weight [BW]; two times daily for 4 days and one time daily for 3 days) or vehicle (n = 12). Mean ± SEM from three independent experiments. (E) Survival of the same mice as in (D). (F) CFU for aerobic (Ae) and anaerobic (An) bacteria, 48 hr after CLP. Red bars represent mean values and dotted circles individual mice. (G) Blood glucose levels in C57BL/6 mice receiving heme (n = 15) (intraperitoneally [i.p.] 30 mg/kg BW) or control protoporphyrin IX (PPIX) (n = 10). Mean ± SEM from three to five independent experiments. (H) Blood glucose levels in Fthlox/lox (n = 8) and Mx1CreFthΔ/Δ (n = 9) mice receiving heme (i.p. 25–30 mg/kg BW). Mean ± SD from two independent experiments. (I) Survival of Fthlox/lox (n = 8) and Mx1CreFthΔ/Δ (n = 9) mice receiving heme (i.p. 25–30 mg/kg BW). (J) Blood glucose levels in C57BL/6 Tlr4+/+ (n = 13) and Tlr4−/− (n = 9) mice receiving heme (i.p. 30 mg/kg BW). Mean ± SEM from three to four independent experiments. (K) Blood glucose levels in C57BL/6 Ifnr1+/+ (n = 7) and Ifnr1−/− (n = 7) mice receiving heme (i.p. 30 mg/kg BW). Mean ± SD from two independent experiments. PC, peritoneal cavity. Numbers in gray in (A)–(D) and (H) are live/total mice at each time point. p < 0.05; ∗∗p < 0.01. See also Figure S4.
Figure S4
Figure S4
FTH Expression and Glucose Metabolism, Related to Figure 2 (a) Food intake in Fthlox/lox and Mx1CreFthΔ/Δ mice before and after CLP. Data are shown as mean and SD from 3 mice per genotype. (b) Blood glucose levels in Fthlox/lox (n = 3) and Mx1CreFthΔ/Δ (n = 3) mice in the first 12 hr after CLP. Mean ± SD, data from 1 experiment. (c) Blood glucose levels in C57BL/6 mice in the first 12 hr after CLP (n = 7) or control sham operation (n = 12). Mean ± SD, data from 3-4 independent experiments. (d) Total heme levels in the peritoneal cavity in C57BL/6 mice before (n = 4) and 3 hr after CLP (n = 3). (e) Blood glucose levels in C57BL/6 mice in the first 8 hr after heme (n = 15) or protoporphyrin IX (PPIX) (n = 10) administration (i.p.; 30 mg/kg BW). Mean ± SEM, data from 3-5 independent experiments. (f) Blood glucose levels in Fthlox/lox (n = 8) and Mx1CreFthΔ/Δ (n = 9) in the first 8 hr after heme administration (i.p.; 25 to 30 mg/kg BW). Mean ± SD from 2 independent experiments. (g) Blood glucose levels in C57BL/6 Tlr4+/+ (n = 13) and Tlr4−/− (n = 9) mice in the first 8 hr after heme administration (i.p.; 30 mg/kg BW). Mean ± SEM from 3-4 independent experiments. (h) Blood glucose levels in C57BL/6 Ifnr1+/+ (n = 7) and Ifnr1−/− (n = 7) mice in the first 8 hr after heme administration (i.p.; 30 mg/kg BW). Mean ± SD from 2 independent experiments. (i) Oral glucose tolerance test (oGTT), (j) pyruvate tolerance test (PTT) and (k) glucagon challenge test (GCT) in Fthlox/lox and Mx1CreFthΔ/Δ mice. Data are shown as mean ± SEM, pooled from 3 independent experiments with n = 3 mice per genotype per experiment. (l) insulin tolerance test (ITT) in Fthlox/lox and Mx1CreFthΔ/Δ mice. Data are shown as mean ± SD, from 1 experiment with n = 5 mice per genotype. (m) Plasma insulin levels in Fthlox/lox and Mx1CreFthΔ/Δ mice after overnight fasting. Data are shown as mean ± SD from 4-5 mice per genotype. (n) Plasma insulin levels in Fthlox/lox and Mx1CreFthΔ/Δ mice before (control; Ctr.) and 48 hr after CLP. Data are shown as mean ± SD from 4-6 mice per genotype, pooled from 2-3 experiments.
Figure 3
Figure 3
FTH Prevents Liver Glucose Metabolism from Shifting Toward Glycolysis in Detriment of Gluconeogenesis (A) Blood glucose in Mx1CreFthΔ/Δ mice subjected to CLP and receiving pyruvate (n = 6) or vehicle (n = 7). Mean ± SD from two independent experiments. Numbers in gray indicate live/total mice at different time points. (B) Survival of the same mice as in (A). (C) Targeted metabolomics of the liver and flux balance analysis for ATP generation using data integration into a reconstructed metabolic network iMM1415 (Sigurdsson et al., 2010). Data are shown as mean ± SD (n = 5 mice per group). DHAP, dihydroxyacetone phosphate; F6P, fructose 6-phosphate; F16P, fructose-1,6-bisphosphate; GAP, glyceraldehyde 3-phosphate; G6P, glucose 6-phosphate; 13bPG, 1,3-bisphosphoglycerate; 2PG, 2-phosphoglycerate; 3PG, 3-phosphoglycerate; PEP, phosphopyruvate. p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001. See also Figure S5 and Tables S1 and S2.
Figure S5
Figure S5
Targeted Amino Acids Metabolomics of the Liver, Related to Figure 3 Data are shown as mean ± SD of 5 mice per group. p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001. NS: non-significant.
Figure 4
Figure 4
FTH Sustains Hepatic G6Pase in Response to Systemic Polymicrobial Infection (A) Volcano plot of mean RNA expression from RNA microarray screen in the liver of Mx1CreFthΔ/Δ versus Fthlox/lox mice, 48 hr after CLP (n = 4 mice per group). (B) Validation of G6pc1 mRNA expression by qRT-PCR in the liver of Mx1CreFthΔ/Δ mice not subjected to CLP (n = 13), 48 hr after CLP (n = 12) versus Fthlox/lox mice not subjected to CLP (n = 11), or 48 hr after CLP (n = 11). Data pooled from three independent experiments. (C and D) Representative western blot of G6pc1 in Mx1CreFthΔ/Δ versus Fthlox/lox mice (C) and relative quantification by densitometry (D) before (Control; Ctr) or 48 hr after CLP (n = 6 per group). (E) Quantification of liver Gpt1 mRNA by qRT-PCR, same mice as (B). (F) Liver G6Pase enzymatic activity, same mice as (B). (G) Quantification of G6PC1 mRNA levels by qRT-PCR in HepG2 cells untreated (−) or treated (+) with heme and/or TNF. Mean ± SEM from eight independent experiments with similar trend. (H) G6PC1 protein levels in HepG2 cells treated as in (G). (I) Relative quantification G6PC1 protein levels by densitometry of western blot from HepG2 cells treated as in (G) and (H). (J) Relative luciferase units (RLU) in HepG2 cells transiently co-transfected with a rat G6pc1 firefly luciferase and CMV Renilla luciferase reporters. Control cells were transfected with a promoterless firefly luciferase reporter. Cells were treated, 48 hr after transfection, with heme and TNF. Data are shown as mean RLU ± SD from four independent experiments with similar trend. (K) Liver mRNA quantification by qRT-PCR in C57BL/6 mice receiving heme (+; n = 8) (i.p. 30 mg/kg BW) or not (−; n = 9). Data pooled from three independent experiments. (L) Liver mRNA quantification by qRT-PCR in Mx1CreFthΔ/Δ versus Fthlox/lox mice receiving heme (+; i.p. 15 mg/kg BW; n = 3 per genotype) or not (−; n = 6–8 per genotype). Data pooled from one to three independent experiments. (M) Relative luciferase units (RLU) in HepG2 cells transiently co-transfected with a rat G6pc1 firefly luciferase and a CMV Renilla luciferase reporters plus a human FTH expression vector. Cells transfected with a promoterless firefly luciferase reporter were used as baseline RLU. Transfected cells were treated 48 hr thereafter with heme and TNF and analyzed 12 hr thereafter. Data shown as mean RLU ± SD from five independent experiments with similar trend. Red bars in (B), (D)–(F), (J), and (K) represent mean values and doted circles indicate individual mice. p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.01. See also Figure S6.
Figure S6
Figure S6
Liver Gluconeogenesis Is Required to Establish Disease Tolerance to Sepsis, Related to Figures 4 and 5 (a) Western Blot of G6PC1 and p21 in HepG2 cells untreated (-) or treated (+) with heme and TNF in the presence (+) or absence (-) of Lactacystin (Lact.) or MG132. Actin was used as loading control. Data are representative of three independent experiments with the same trend. (b) G6Pase enzymatic activity in HepG2 cells transduced (+) or not (-) with a G6PC1 Rec.Ad. and when indicated (+) co-transduced with a FTH Rec.Ad. Transduction with a LacZ Rec. Ad. was used as a control. NT: Not transduced. Cells were treated (+) or not (-) with heme and TNF 72 hr after Rec.Ad. transduction. Data are shown as mean ± SD, pooled from 2 independent experiments with four replicates each. (c) Temperature and (d) weight of G6pc1lox/lox (n = 12) and AlbCreERT2G6pc1Δ/Δ (n = 12) mice subjected to CLP. Data are shown as mean ± SEM, pooled from 3 independent experiments. (e) Blood glucose and (f) clinical severity score in Control (C57BL/6; n = 7) and AlbCreERT2G6pc1Δ/Δ (n = 5) mice subjected to CLP. Mean ± SD pooled from 2 independent experiments. (g) Serological markers of organ injury in C57BL/6 (n = 7) and AlbCreERT2G6pc1Δ/Δ (n = 5) mice 6 hr mice after CLP. (h) H&E stained paraffin sections representative of at least four G6pc1lox/lox and AlbCreERT2G6pc1Δ/Δ mice 9 hr after PCI. B: bronchus; CV: central vein; G: glomerulus. Magnification 400x. (i) Temperature and (h) weight and (j) blood glucose levels in G6pc1lox/lox (n = 6) and AlbCreERT2G6pc1Δ/Δ (n = 7) mice receiving heme (i.p; 30 mg/kg BW). Mean ± SD from 2 independent experiments. p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001.
Figure 5
Figure 5
Liver Gluconeogenesis Is Critical to Establish Disease Tolerance to Sepsis (A) G6pc1 protein expression in the liver of control (G6pc1lox/lox; Ctr) and AlbCreERT2G6pc1Δ/Δ (G6pc1Δ/Δ) mice. (B) Blood glucose levels of G6pc1lox/lox (n = 12) and AlbCreERT2G6pc1Δ/Δ (n = 12) mice subjected to CLP. Data are shown as mean ± SEM from three independent experiments. (C) Survival of control (G6pc1lox/lox; n = 10) and AlbCreERT2G6pc1Δ/Δ (n = 10) mice subjected to CLP. Data were pooled from two independent experiments with similar trend. (D) Blood glucose of control (C57BL/6; n = 7) and AlbCreERT2G6pc1Δ/Δ (n = 5) mice subjected to PCI. Data are shown as mean ± SD from two independent experiments with the same trend. (E) Survival of control (C57BL/6; n = 10) and AlbCreERT2G6pc1Δ/Δ (n = 8) subjected to PCI. Data pooled from three independent experiments with similar trend. (F) CFU for aerobic (Ae) and anaerobic (An) bacteria, 6 hr after PCI. Red bars represent mean values and dotted circles represent individual mice. PC, peritoneal cavity. (G) Blood glucose levels in G6pc1lox/lox (n = 6) and AlbCreERT2G6pc1Δ/Δ (n = 7) mice receiving heme (i.p. 30 mg/kg BW). Mean ± SD from two independent experiments. (H) Survival of same mice as (G). (I) Blood glucose levels in G6pc1lox/lox (n = 6) and AlbCreERT2G6pc1Δ/Δ (n = 9) mice receiving LPS (i.p. 5 mg/kg BW). Mean ± SD from two independent experiments. (J) Survival of same mice as (I). (K) Blood glucose levels in G6pc1lox/lox (n = 9) and AlbCreERT2Gpc1Δ/Δ (n = 10) mice receiving poly(I:C) (intra-retro orbital [i.r.o.] 30 mg/kg BW). Mean ± SD from two independent experiments. (L) Survival of same mice as (K). Numbers in gray (B, D, G, I, and K) are live/total mice at each time point. p < 0.05; ∗∗p < 0.01. See also Figure S6.
Figure 6
Figure 6
FTH Overexpression or Ferritin Administration Induce Disease Tolerance to Sepsis (A) Survival of C57BL/6 mice transduced 48 hr before severe CLP with FTH Rec.Ad. (n = 11), ferroxidase-deficient FTH Rec.Ad. (FTHm; n = 11), LacZ Rec.Ad. (n = 12), or receiving vehicle (PBS; n = 19). Data pooled from six independent experiments with similar trend. (B) CFU for aerobic (Ae) and anaerobic (An) bacteria, 12 hr after CLP in mice treated as in (A). (C) Representative western blot in HepG2 cells transduced with LacZ, FTH, or mutated FTH (FTHm) Rec.Ad. (D and E) Densitometry of G6PC1 (D) and FTH protein (E) expression normalized to α-tubulin (n = 4 per group). (F) Expression of G6pc1 mRNA quantified by qRT-PCR in HepG2 cells exposed (+) or not (−) to heme, TNF, and deferoxamine (DFO). Mean ± SEM from three independent experiments done in duplicates. (G) Survival of C57BL/6 mice receiving apoferritin (n = 16), ferritin (n = 10), BSA (n = 12), or saline (n = 12), 24 hr before severe CLP. Data pooled from five independent experiments. (H) CFU for aerobic (Ae) and anaerobic (An) bacteria 12 hr after severe CLP in mice treated as in (G). Data from three independent experiments. (I) Survival of C57BL/6 mice receiving apoferritin (n = 22), BSA (n = 20), or saline (n = 16) 6 hr after severe CLP. Data pooled from seven independent experiments. Red bars represent mean values and dotted circles represent individual mice (B and G). PC, peritoneal cavity; NS, non-significant. p < 0.05, ∗∗p < 0.01. See also Figure S7.
Figure S7
Figure S7
FTH Overexpression and Apo-Ferritin Administration Induce Disease Tolerance to Sepsis, Related to Figure 6 (a) Serological markers of organ injury, before (Control; Ctr) and 12 hr after severe CLP in C57BL/6 mice transduced with Rec.Ad. encoding FTH, ferroxidase-deficient FTH (FTHm), LacZ or receiving vehicle (PBS). Data are shown as mean ± SD from n = 4-5 mice per group, pooled from 3 independent experiments. (b) Serological markers of organ injury, before (Control; Ctr) and 12 hr after severe CLP C57BL/6 mice receiving apoferritin, ferritin, bovine serum albumin (BSA) or saline. Data are shown as mean ± SD from n = 4-5 mice per group, samples were pooled from 3 independent experiments. p < 0.05, ∗∗p < 0.01; ∗∗∗∗p < 0.001.
Figure 7
Figure 7
Antioxidants Bypass the Requirement of FTH in the Establishment of Normoglycemia and Disease Tolerance to Sepsis (A–C) Relative weight (A), blood glucose (B), and survival (C) of Mx1CreFthΔ/Δ mice subjected to CLP and receiving NAC (n = 7; 15 mg/kg) or vehicle (n = 6). Data pooled from two independent experiments. (D) Colony forming units (CFU) for aerobic (Ae) and anaerobic (An) bacteria, 48 hr after CLP. PC, peritoneal cavity. Red bars represent mean values and doted circles represent individual mice. Pooled from two independent experiments. (E) Expression of G6PC1 mRNA quantified by qRT-PCR in HepG2 cells exposed (+) or not (−) to heme, TNF, and/or NAC. Data shown as mean ± SD from four independent experiments. (F and G) Blood glucose (F) and survival (G) of Mx1CreFthΔ/Δ mice subjected to CLP and receiving BHA (n = 11; 50 mg/kg) or vehicle (n = 9). Data shown as mean ± SD. Pooled from three independent experiments. (H–J) Relative weight (H), blood glucose (I), and survival (J) of AlbCreERT2G6pc1Δ/Δ mice subjected to CLP and receiving NAC (n = 5) or vehicle (n = 5). Mean ± SD from one experiment. NS, non-significant. p < 0.05, ∗∗p < 0.01. Numbers in gray (A, B, F, I, and J) indicate live/total mice.

Comment in

Similar articles

See all similar articles

Cited by 48 articles

See all "Cited by" articles

References

    1. Adamzik M., Hamburger T., Petrat F., Peters J., de Groot H., Hartmann M. Free hemoglobin concentration in severe sepsis: methods of measurement and prediction of outcome. Crit. Care. 2012;16:R125. - PMC - PubMed
    1. Angus D.C., van der Poll T. Severe sepsis and septic shock. N. Engl. J. Med. 2013;369:2063. - PubMed
    1. Berberat P.O., Katori M., Kaczmarek E., Anselmo D., Lassman C., Ke B., Shen X., Busuttil R.W., Yamashita K., Csizmadia E. Heavy chain ferritin acts as an antiapoptotic gene that protects livers from ischemia reperfusion injury. FASEB J. 2003;17:1724–1726. - PubMed
    1. Clausen B.E., Burkhardt C., Reith W., Renkawitz R., Förster I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 1999;8:265–277. - PubMed
    1. Clottes E., Burchell A. Three thiol groups are important for the activity of the liver microsomal glucose-6-phosphatase system. Unusual behavior of one thiol located in the glucose-6-phosphate translocase. J. Biol. Chem. 1998;273:19391–19397. - PubMed
Feedback