Research ArticleMetabolism

Controlled-release mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates

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Science Translational Medicine  02 Oct 2019:
Vol. 11, Issue 512, eaay0284
DOI: 10.1126/scitranslmed.aay0284
  • Fig. 1 CRMP reduces hepatic triglycerides in high-fat fructose-fed cynomolgus macaques.

    (A) Experimental outline of CRMP treatment in cynomolgus macaques. (B to M) Body weight (B), fasting plasma glucose (FPG) (C), EGP (D), plasma triglycerides (E), total cholesterol (TC) (F), LDL-C (G), HDL-C (H), ALT (I), AST (J), BUN (K), creatinine (L), and hepatic triglyceride content (M) in high-fat fructose-fed cynomolgus macaques before (pre-CRMP) and after CRMP (0.8 mg/kg BID) treatment for 6 weeks (post-CRMP). Data are means ± SD. In (B) to (L), n = 6 per treatment group. In (M), n = 4 per treatment group. *P ≤ 0.05 by paired Student’s t test (baseline versus treatment).

  • Fig. 2 CRMP treatment reduces plasma triglycerides, VLDL-C, and LDL-C in dysmetabolic rhesus macaques.

    (A) Experimental outline of the CRMP efficacy study in dysmetabolic rhesus macaques. (B) Citrate synthase flux (VCS) in dysmetabolic rhesus macaques after acute treatment with CRMP (5 mg/kg; n = 10) or vehicle control (n = 6). *P ≤ 0.05 by unpaired Student’s t test. (C to N) Body weight (C), total fat mass (D), total lean mass (E), fasting plasma triglycerides (F), total cholesterol (TC) (G), VLDL-C (H), LDL-C (I), HDL-C (J), AST (K), ALT (L), BUN (M), and creatinine (N) in dysmetabolic rhesus macaques before (baseline) and after treatment with CRMP (5 mg/kg; n = 12) or vehicle control (n = 6) for 6 weeks (treatment). In (D), (G), and (I), *P ≤ 0.05 by paired Student’s t test (baseline versus treatment). In (F) and (H), *P ≤ 0.05 by Wilcoxon matched-pairs signed rank test (baseline versus treatment). Data are means ± SD.

  • Fig. 3 CRMP treatment reduces hepatic triglycerides and EGP in dysmetabolic rhesus macaques.

    Hepatic triglycerides (A), fasting plasma glucose (FPG) (B), insulin (C), HOMA-IR (D), EGP (E), hepatic sensitivity index (F), pyruvate carboxylase flux (VPC) (G), and β-OHB turnover (H) in dysmetabolic rhesus macaques before (baseline) and after treatment with CRMP (5 mg/kg; n = 12) or vehicle control (n = 6) for 6 weeks (treatment). *P ≤ 0.05 by paired Student’s t test (baseline versus treatment). In all panels, data are means ± SD.

  • Fig. 4 Validation of PINTA to assess mitochondrial metabolism in nonhuman primates.

    (A) Experimental outline of [3-13C]lactate infusion in dysmetabolic rhesus macaques (n = 5). (B and C) VPC/VCS (B) and VPC/VEGP in the plasma (P1 and P2) and livers of dysmetabolic rhesus macaques infused with [3-13C]lactate [10 μmol/(kg-min)] for 190 min as assessed by PINTA. (D and E) VPC/VCS (D) and VPC/VEGP (E) in the livers of dysmetabolic rhesus macaques infused with [3-13C]lactate [10 μmol/(kg-min)] for 190 min as assessed by ex vivo NMR (black bars) and PINTA (gray bars). (F to I) VPDH/VCS (F), VPDH (G) VPK/VPC + VPDH (H), and VPK (I) in the livers of dysmetabolic rhesus macaques infused with [3-13C]lactate [10 μmol/(kg-min)] for 190 min. In (B) to (I), data are means ± SD. Each different color dot represents an individual animal.

  • Table 1 Characteristics of rhesus macaque cohorts.
    StudyAnimal
    ID
    SexAge
    (years)
    Body weight
    (kg)
    Treatment
    CRMP dose
    escalation
    M632F1612.1
    M254F268.3
    CRMP efficacyM956F913.74Vehicle
    75PF1610.38Vehicle
    88JF195.92Vehicle
    35SF1610.68Vehicle
    38FF228.34Vehicle
    M767M1315.65Vehicle
    031F209.30CRMP
    12KF1910.20CRMP
    M619F1710.20CRMP
    90JF198.10CRMP
    98LF1810.08CRMP
    AC94F189.40CRMP
    AH78F1511.74CRMP
    AL33F1311.06CRMP
    M254F277.52CRMP
    M632F1713.30CRMP
    M741M1416.93CRMP
    68KF197.92CRMP
    Acute CRMP
    treatment
    031F219.49
    M649F1810.97
    90JF208.5
    M741M1517.58
    98LF1910.47
    AL33F1511.43
    M632F1813.74
    M956F1015.09
    75PF189.86
    M787M1415.98
    PINTA validationAH78F168.26
    15GF224.40
    33720F178.04
    68KF215.90
    37682M1315.84
  • Table 2 Characteristics of cynomolgus macaque cohort.
    StudyAnimal IDSexAge (years)Body weight (kg)
    CRMP efficacyA1M1010.3
    A2M108.9
    A3M138.85
    A4M109.7
    A5M1011.85
    A6M1010.15

Supplementary Materials

  • stm.sciencemag.org/cgi/content/full/11/512/eaay0284/DC1

    Fig. S1. Safety and efficacy profile of CRMP-treated, high-fat, fructose-fed cynomolgus macaques.

    Fig. S2. Oral CRMP dose escalation study in dysmetabolic rhesus macaques.

    Fig. S3. Plasma DNP concentrations in dysmetabolic rhesus macaques.

    Fig. S4. CRMP treatment does not alter oxidative stress in dysmetabolic rhesus macaques.

    Fig. S5. CRMP treatment does not alter whole-body glucose tolerance in dysmetabolic rhesus macaques.

    Fig. S6. Hepatic mitochondrial fluxes in dysmetabolic rhesus macaques treated with CRMP.

  • This PDF file includes:

    • Fig. S1. Safety and efficacy profile of CRMP-treated, high-fat, fructose-fed cynomolgus macaques.
    • Fig. S2. Oral CRMP dose escalation study in dysmetabolic rhesus macaques.
    • Fig. S3. Plasma DNP concentrations in dysmetabolic rhesus macaques.
    • Fig. S4. CRMP treatment does not alter oxidative stress in dysmetabolic rhesus macaques.
    • Fig. S5. CRMP treatment does not alter whole-body glucose tolerance in dysmetabolic rhesus macaques.
    • Fig. S6. Hepatic mitochondrial fluxes in dysmetabolic rhesus macaques treated with CRMP.

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