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Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers.

Park HW, Park H, Semple IA, Jang I, Ro SH, Kim M, Cazares VA, Stuenkel EL, Kim JJ, Kim JS, Lee JH - Nat Commun (2014)

Bottom Line: Here we show that a chronic increase of the cytosolic calcium concentration in hepatocytes during obesity and lipotoxicity attenuates autophagic flux by preventing the fusion between autophagosomes and lysosomes.Such treatment successfully increases autophagosome-lysosome fusion in liver, preventing accumulation of protein inclusions and lipid droplets and suppressing inflammation and insulin resistance.As calcium channel blockers have been safely used in clinics for the treatment of hypertension for more than 30 years, our results suggest they may be a safe therapeutic option for restoring autophagic flux and treating metabolic pathologies in obese patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.

ABSTRACT
Autophagy deregulation during obesity contributes to the pathogenesis of diverse metabolic disorders. However, without understanding the molecular mechanism of obesity interference in autophagy, development of therapeutic strategies for correcting such defects in obese individuals is challenging. Here we show that a chronic increase of the cytosolic calcium concentration in hepatocytes during obesity and lipotoxicity attenuates autophagic flux by preventing the fusion between autophagosomes and lysosomes. As a pharmacological approach to restore cytosolic calcium homeostasis in vivo, we administered the clinically approved calcium channel blocker verapamil to obese mice. Such treatment successfully increases autophagosome-lysosome fusion in liver, preventing accumulation of protein inclusions and lipid droplets and suppressing inflammation and insulin resistance. As calcium channel blockers have been safely used in clinics for the treatment of hypertension for more than 30 years, our results suggest they may be a safe therapeutic option for restoring autophagic flux and treating metabolic pathologies in obese patients.

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Verapamil reduces liver inflammation and improves metabolic homeostasis4 month-old C57BL/6 male mice kept on HFD for two months were subjected to daily administration of PBS (Con, n = 4) or verapamil (Ver, 25 mg kg−1 body weight, i.p., n = 3) for 10 days. LFD-kept mice of same age (n = 5) were used as a negative control. (a, b) Liver sections were subjected to F4/80 immunostaining, which visualizes macrophage infiltration and hematoxylin counterstaining (a). F4/80-positive areas were quantified (b). (c–f) Glucose tolerance tests (GTT, c, d) and insulin tolerance tests (ITT, e, f) were conducted using indicated mice (c, e). Area-under-the-curve (AUC) was quantified from GTT and ITT data (d, f). (g) Serum insulin levels were measured from indicated mice before (Basal) and 10 min after (Glucose-stimulated) glucose injection (n = 4). (h, i) Pancreas sections were analyzed by hematoxylin and eosin (H&E) staining (h). Islet areas were quantified (i) (n = 4). Scale bar, 200 μm (a), 100 μm (h). All data are shown as mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001 (Student’s t test).
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Figure 6: Verapamil reduces liver inflammation and improves metabolic homeostasis4 month-old C57BL/6 male mice kept on HFD for two months were subjected to daily administration of PBS (Con, n = 4) or verapamil (Ver, 25 mg kg−1 body weight, i.p., n = 3) for 10 days. LFD-kept mice of same age (n = 5) were used as a negative control. (a, b) Liver sections were subjected to F4/80 immunostaining, which visualizes macrophage infiltration and hematoxylin counterstaining (a). F4/80-positive areas were quantified (b). (c–f) Glucose tolerance tests (GTT, c, d) and insulin tolerance tests (ITT, e, f) were conducted using indicated mice (c, e). Area-under-the-curve (AUC) was quantified from GTT and ITT data (d, f). (g) Serum insulin levels were measured from indicated mice before (Basal) and 10 min after (Glucose-stimulated) glucose injection (n = 4). (h, i) Pancreas sections were analyzed by hematoxylin and eosin (H&E) staining (h). Islet areas were quantified (i) (n = 4). Scale bar, 200 μm (a), 100 μm (h). All data are shown as mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001 (Student’s t test).

Mentions: Liver inflammation, characterized by increased macrophage infiltration into the liver, is a hallmark of NASH pathologies in addition to accumulation of lipid droplets and protein inclusions52. Because liver inflammation can be provoked by either HFD-induced obesity53 or genetic inhibition of autophagy26, 54, we were interested in the effect that calcium channel blockers may have on resolving obesity-associated liver inflammation. Verapamil administration was found to reduce liver inflammation in livers from HFD-kept obese mice, as manifested by decreased macrophage number that is comparable to LFD-kept lean mice (Fig. 6a, b). These results add more evidence that calcium channel blockers can have a potential as therapeutics for NASH pathologies.


Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers.

Park HW, Park H, Semple IA, Jang I, Ro SH, Kim M, Cazares VA, Stuenkel EL, Kim JJ, Kim JS, Lee JH - Nat Commun (2014)

Verapamil reduces liver inflammation and improves metabolic homeostasis4 month-old C57BL/6 male mice kept on HFD for two months were subjected to daily administration of PBS (Con, n = 4) or verapamil (Ver, 25 mg kg−1 body weight, i.p., n = 3) for 10 days. LFD-kept mice of same age (n = 5) were used as a negative control. (a, b) Liver sections were subjected to F4/80 immunostaining, which visualizes macrophage infiltration and hematoxylin counterstaining (a). F4/80-positive areas were quantified (b). (c–f) Glucose tolerance tests (GTT, c, d) and insulin tolerance tests (ITT, e, f) were conducted using indicated mice (c, e). Area-under-the-curve (AUC) was quantified from GTT and ITT data (d, f). (g) Serum insulin levels were measured from indicated mice before (Basal) and 10 min after (Glucose-stimulated) glucose injection (n = 4). (h, i) Pancreas sections were analyzed by hematoxylin and eosin (H&E) staining (h). Islet areas were quantified (i) (n = 4). Scale bar, 200 μm (a), 100 μm (h). All data are shown as mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001 (Student’s t test).
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Figure 6: Verapamil reduces liver inflammation and improves metabolic homeostasis4 month-old C57BL/6 male mice kept on HFD for two months were subjected to daily administration of PBS (Con, n = 4) or verapamil (Ver, 25 mg kg−1 body weight, i.p., n = 3) for 10 days. LFD-kept mice of same age (n = 5) were used as a negative control. (a, b) Liver sections were subjected to F4/80 immunostaining, which visualizes macrophage infiltration and hematoxylin counterstaining (a). F4/80-positive areas were quantified (b). (c–f) Glucose tolerance tests (GTT, c, d) and insulin tolerance tests (ITT, e, f) were conducted using indicated mice (c, e). Area-under-the-curve (AUC) was quantified from GTT and ITT data (d, f). (g) Serum insulin levels were measured from indicated mice before (Basal) and 10 min after (Glucose-stimulated) glucose injection (n = 4). (h, i) Pancreas sections were analyzed by hematoxylin and eosin (H&E) staining (h). Islet areas were quantified (i) (n = 4). Scale bar, 200 μm (a), 100 μm (h). All data are shown as mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001 (Student’s t test).
Mentions: Liver inflammation, characterized by increased macrophage infiltration into the liver, is a hallmark of NASH pathologies in addition to accumulation of lipid droplets and protein inclusions52. Because liver inflammation can be provoked by either HFD-induced obesity53 or genetic inhibition of autophagy26, 54, we were interested in the effect that calcium channel blockers may have on resolving obesity-associated liver inflammation. Verapamil administration was found to reduce liver inflammation in livers from HFD-kept obese mice, as manifested by decreased macrophage number that is comparable to LFD-kept lean mice (Fig. 6a, b). These results add more evidence that calcium channel blockers can have a potential as therapeutics for NASH pathologies.

Bottom Line: Here we show that a chronic increase of the cytosolic calcium concentration in hepatocytes during obesity and lipotoxicity attenuates autophagic flux by preventing the fusion between autophagosomes and lysosomes.Such treatment successfully increases autophagosome-lysosome fusion in liver, preventing accumulation of protein inclusions and lipid droplets and suppressing inflammation and insulin resistance.As calcium channel blockers have been safely used in clinics for the treatment of hypertension for more than 30 years, our results suggest they may be a safe therapeutic option for restoring autophagic flux and treating metabolic pathologies in obese patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.

ABSTRACT
Autophagy deregulation during obesity contributes to the pathogenesis of diverse metabolic disorders. However, without understanding the molecular mechanism of obesity interference in autophagy, development of therapeutic strategies for correcting such defects in obese individuals is challenging. Here we show that a chronic increase of the cytosolic calcium concentration in hepatocytes during obesity and lipotoxicity attenuates autophagic flux by preventing the fusion between autophagosomes and lysosomes. As a pharmacological approach to restore cytosolic calcium homeostasis in vivo, we administered the clinically approved calcium channel blocker verapamil to obese mice. Such treatment successfully increases autophagosome-lysosome fusion in liver, preventing accumulation of protein inclusions and lipid droplets and suppressing inflammation and insulin resistance. As calcium channel blockers have been safely used in clinics for the treatment of hypertension for more than 30 years, our results suggest they may be a safe therapeutic option for restoring autophagic flux and treating metabolic pathologies in obese patients.

Show MeSH
Related in: MedlinePlus