Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production

Christopher Hine, Hyo-Jeong Kim, Yan Zhu, Eylul Harputlugil, Alban Longchamp, Marina Souza Matos, Preeti Ramadoss, Kevin Bauerle, Lear Brace, John M Asara, C Keith Ozaki, Sheue-Yann Cheng, Subhankar Singha, Kyo Han Ahn, Alec Kimmelman, Ffolliott M Fisher, Pavlos Pissios, Dominic J Withers, Colin Selman, Rui Wang, Kelvin Yen, Valter D Longo, Pinchas Cohen, Andrzej Bartke, John J Kopchick, Richard Miller, Anthony N Hollenberg, James R Mitchell, Christopher Hine, Hyo-Jeong Kim, Yan Zhu, Eylul Harputlugil, Alban Longchamp, Marina Souza Matos, Preeti Ramadoss, Kevin Bauerle, Lear Brace, John M Asara, C Keith Ozaki, Sheue-Yann Cheng, Subhankar Singha, Kyo Han Ahn, Alec Kimmelman, Ffolliott M Fisher, Pavlos Pissios, Dominic J Withers, Colin Selman, Rui Wang, Kelvin Yen, Valter D Longo, Pinchas Cohen, Andrzej Bartke, John J Kopchick, Richard Miller, Anthony N Hollenberg, James R Mitchell

Abstract

Decreased growth hormone (GH) and thyroid hormone (TH) signaling are associated with longevity and metabolic fitness. The mechanisms underlying these benefits are poorly understood, but may overlap with those of dietary restriction (DR), which imparts similar benefits. Recently we discovered that hydrogen sulfide (H2S) is increased upon DR and plays an essential role in mediating DR benefits across evolutionary boundaries. Here we found increased hepatic H2S production in long-lived mouse strains of reduced GH and/or TH action, and in a cell-autonomous manner upon serum withdrawal in vitro. Negative regulation of hepatic H2S production by GH and TH was additive and occurred via distinct mechanisms, namely direct transcriptional repression of the H2S-producing enzyme cystathionine γ-lyase (CGL) by TH, and substrate-level control of H2S production by GH. Mice lacking CGL failed to downregulate systemic T4 metabolism and circulating IGF-1, revealing an essential role for H2S in the regulation of key longevity-associated hormones.

Keywords: FGF21; IGF-1; IRS-1; autophagy; cystathionine γ-lyase; growth hormone; hydrogen sulfide; hypopituitary dwarfism; longevity; thyroid hormone.

Copyright © 2017 Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Increased Hepatic H2S Production in Long-Lived Hypopituitary Dwarf Mice In Vivo (A–D) Hepatic CGL and CBS mRNA expression (n = 3/group) (A), protein expression (n = 3/group) (B), H2S production capacity via the lead sulfide method (n = 3/group) (C), and endogenous H2S production via two-photon florescence microscopy (n = 3/group) (D) in male and female WT or Snell dwarf mice as indicated. Scale bar, 25 μm. Asterisk indicates the significance of the difference between genotypes within sex; ∗p < 0.05. (E) Liver H2S production capacity in 18-month-old female Ames dwarf or WT mice treated +/− growth hormone during postnatal development at weeks 2-8 (n = 9–14/group). The asterisk indicates the significance of the difference between the WT+Saline control group and experimental group, and the # sign indicates the significance of the difference between +Saline and +GH; ∗/#p < 0.05. (F) Liver H2S production capacity in mice treated with saline control or lanreotide (n = 4/group). The asterisks indicate the significance of the difference between treatment groups; ∗p < 0.05. Error bars are ± SEM. See also Figure S1.
Figure 2
Figure 2
Growth Hormone Signaling Inhibits Hepatic H2S Production In vivo (A–C) Hepatic CGL and CBS mRNA expression (n = 3/group) (A), protein expression (n = 3/group) (B), and H2S production capacity (n = 3/group) (C) in male and female growth hormone receptor knockout (GHRKO) mice. The asterisk indicates the significance of the difference between genotypes within sex; ∗p < 0.05. (D) Liver H2S production capacity (n = 8/group) in WT mice treated for 2 weeks with recombinant IGF-1, GH, or saline vehicle as indicated. The asterisk indicates the significance of the difference between GH and saline treatment; ∗p < 0.05. (E and F) Liver H2S production capacity in male and female IRS-1 WT or KO mice (n = 4–11/group) (E) and in male FGF21 WT or overexpressing (OE) mice (n = 6/group) (F). The asterisk indicates the significance of the difference between genotypes within sex; ∗p < 0.05. Error bars are ± SEM. See also Figure S2.
Figure 3
Figure 3
Growth Hormone Receptor Signaling Inhibits Hepatic H2S Production In Vitro (A–C) Endogenous H2S production in primary mouse hepatocytes as measured via two-photon fluorescent microscopy under different medium conditions: (A) +/−growth serum and +/−GH, with the asterisk indicating the significance of the difference between Complete and −Serum, and the # sign indicating the significance of the difference between −Serum and −Serum+GH, ∗/#p < 0.05; (B) +/−growth serum, +/−GH, +/−AZD1480, with the asterisk indicating the significance of the difference between Complete and −Serum in each group, and the # sign indicating the significance of the difference between −Serum (−) (no addition) and −Serum+ZD1480; and the $ sign indicating the significance of the difference between +GH and +GH+ZD1480 for both Complete and −Serum conditions, ∗/#/$p < 0.05; (C) +/−FGF21 in Complete medium containing serum, with the asterisk indicating the significance of the difference between Complete and Complete+FGF21; ∗p < 0.05. (D) mRNA expression of Igf-I, Cgl, and Cbs in mouse primary hepatocytes. The asterisk indicates the significance of the difference between +GH and +GH+ZD1480; ∗p < 0.05. (E and F) Endogenous H2S production in mouse primary hepatocytes by florescent microscopy after overnight treatment under the indicated medium conditions followed by addition of the P3 probe for 1 hr. The asterisk indicates the significance of the difference between Complete and −Serum, and the # sign indicates the significance of the difference between −Serum and −Serum+BAF (E), or −Serum−SAA and −Serum−SAA+CQ (F); ∗#p < 0.05. (G and H) Endogenous H2S production in Hepa1-6 cells with or without knockdown of autophagy components ATG5 and ATG7 by shRNA (G) or in MEFs by genetic knockout of ATG5 and ATG7 (H) detected by UV spectrophotometry after overnight treatment with or without serum followed by addition of the P3 probe for 1 hr. The asterisk indicates the significance of the difference between Complete and −Serum in the Control group, and the # sign indicates the significance of the difference between −Serum Control and −Serum ATG5 deficient or −Serum ATG7 deficient; ∗/#p < 0.05. Each experiment was repeated at least three times. Scale bars, 100 μm (A–C, E, and F). Error bars are ± SEM. See also Figure S3.
Figure 4
Figure 4
Hypothyroidism Increases and Thyroid Hormone Represses Hepatic H2S Production In Vivo (A–D) mRNA expression (n = 4) (A), protein expression (n = 3) (B), H2S production capacity (n = 4) (C), and transmethylation/transsulfuration metabolite levels by liquid chromatography-tandem mass spectrometry (n = 4) (D) in livers of mice under hypo- (PTU+Saline), hyper- (PTU+high dose T3), and eu-(PTU+low dose T3) thyroid states. The asterisks indicate the significance of the difference from the hypothyroid state (PTU+Saline); ∗p < 0.05. (E–G) Analysis of TH-responsive and sulfur amino acid metabolism-associated mRNA levels (n = 4–6) (E), protein expression (n = 5) (F), and H2S production capacity (n = 5) (G) in livers of mice treated with T3 (hyperthyroid) versus vehicle (saline) control (euthyroid). The asterisk indicates the significance of the difference between vehicle and +T3 groups; ∗p < 0.05. Error bars are ± SEM. See also Figure S4.
Figure 5
Figure 5
Thyroid Hormone Signaling through TRβ Represses Hepatic H2S Production In Vivo (A–C) Analysis of TH-responsive and sulfur amino acid metabolism-associated mRNA levels (n = 4–6) (A), protein expression (n = 6) (B), and H2S production capacity (n = 5) (C) in livers of mice treated with GC-1 versus vehicle (saline) control. The asterisk indicates the significance of the difference between vehicle (saline) control (euthyroid) and +GC-1 groups (hyperthyroid); ∗p < 0.05. (D and E) Liver CBS and CGL protein expression (D) and H2S production capacity (E) in mice with indicated TRβ status (WT, homozygous WT; TRβPV/+, Het; TRβPV/PV, homozygous mutant; n = 4–5/group). The asterisk indicates the significance of the difference between WT and TRβPV/PV, and the # sign indicates the significance of the difference between TRβPV/+ and TRβPV/PV; ∗/#p < 0.05. (F) Fold enrichment of TRβ binding to genetic regulator elements in sulfur amino acid metabolism and H2S producing genes in the livers of mice infected with Ad-GFP (control) or Ad-TRβ while on PTU diets +/−T3 injection as indicated (n = 5/group). The asterisk indicates the significance of the difference between the Ad-GFP PTU and Ad-TRβ PTU or Ad-TRβ T3 groups, and the # sign indicates the significance of the difference between the Ad-TRβ PTU and Ad-TRβ T3 groups; ∗/#p < 0.05. (G and H) Liver ATF4 protein expression in mice due to PTU/T3 administration (G) (n = 4/group) or TRβ mutations (H) (n = 4–5/group). The asterisks indicate the significance of the difference between Hyper-T and Eu-T or Hypo-T (G), or WT and TRβPV/+ or TRβPV/PV (H), and the # sign indicates the significance of the difference between TRβPV/+ and TRβPV/PV (H), ∗/#p < 0.05. Error bars are ± SEM. See also Figure S5.
Figure 6
Figure 6
Additive Suppression of Hepatic H2S Production by TH and GH In Vitro (A–C) mRNA levels (n = 3) (A), protein expression (n = 3) (B), and endogenous H2S production (n = 3) (C) in TH-responsive Hepa1-6 cells treated with T3 at the indicated concentration. The asterisk indicates the significance of the difference between vehicle control and T3 treatment and the hash indicates the significance of the difference between different T3 dosage groups; ∗/#p < 0.05. (D) Endogenous H2S production in TH-responsive Hepa1-6 cells grown in Complete medium or −Serum medium +/−GH +/−T3. The asterisk indicates the significance of the difference between Complete and −Serum within the GH/T3 treatment group, and the # sign indicates the significance of the difference between “w/out Additions” and +GH, +T3, or +GH+T3 groups within the −Serum grouping; ∗/#p < 0.05. Scale bars, 100 μm (C and D). Error bars are ± SEM. See also Figure S6.
Figure 7
Figure 7
CGL/H2S Is Required for Negative Regulation of TH and GH/IGF-I Signaling (A and B) Western blot analysis of H2S-producing enzymes CGL, CBS, and 3MST (n = 3) (A) and H2S production capacity in livers of CGL WT and KO mice on Normal and PTU diets (n = 4–5) (B). The asterisk indicates the significance of the difference relative to CGL WT mice on the Normal diet; ∗p < 0.05. (C) Serum T4 levels over a 3-week time course of Normal versus PTU diets in CGL WT and KO mice as indicated (n = 4–5). (D) Pituitary mRNA expression of TSHα and TSHβ in CGL WT and KO mice after 3 weeks of Normal or PTU diet (n = 4–5). The asterisk indicates the significance of difference between diets within genotype, and the # sign indicates the significance of difference between CGL WT and CGL KO mice on the PTU diet; ∗/#p < 0.05. (E) Serum TSH levels after 3 weeks of Normal or PTU diet in CGL WT and KO mice (n = 4–5). The asterisk indicates the significance of difference between diets within genotype, and the # sign indicates the significance of difference between CGL WT and CGL KO mice on the PTU diet; ∗/#p < 0.05. (F) Percent change in serum T4 levels after 3 days of fasting in CGL WT and CGL KO mice (n = 3–4). The asterisk indicates the significance of the difference between day 0 and day 3 T4 levels; ∗p < 0.05. (G–I) Pituitary GH mRNA expression (n = 4–5) (G), liver GHR and IGF-I mRNA expression (n = 4–5) (H), and serum IGF-1 (n = 4–5) (I) in CGL WT and KO mice after 3 weeks on a Normal or PTU diet as indicated. The asterisk indicates the significance of the difference between diets within genotype, and the # sign indicates the significance of the difference between genotypes on the PTU diet; ∗/#p < 0.05. (J) Fold change in serum IGF-I between day 0 and day 3 of a 3-day fast in CGL WT and KO mice (n = 3–4/group). The asterisk indicates the significance of the difference between day 3 and day 0; ∗p < 0.05. (K) Serum IGF-1 levels in mice 7 days after adenoviral infection with Ad-Null control or Ad-CGL overexpression adenovirus expressed relative to Ad-Null control (n = 4/group). The asterisk indicates the significance of the difference between Ad-Null and Ad-CGL; ∗p < 0.05. (L) Fold change in serum IGF-1 after a 2-day fast in female CGL WT and KO mice with +/−NaHS supplementation in the CGL KOs (n = 4–5/group). The asterisks indicate the significance of the difference between serum IGF-1 levels on day 2 compared with day 0; ∗p < 0.05. (M) Relationship between diet, GH/TH, and H2S production. Error bars are ± SEM. See also Figure S7.

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