Vinblastine‐induced autophagocytosis: effects on liver glycogen

Hirsimäki, Pirkko

doi:10.1016/0014-5793(83)80349-4

Cited by 4 publications

(2 citation statements)

References 15 publications

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“…These observations support the general hypothesis that accumulation of misfolded proteins is associated with dysfunction of diverse cellular pathways (3,4,24,25). Based on these concepts and the knowledge that among other changes, autophagy interferes with glycogen storage and/or metabolism (26)(27)(28)(29), we hypothesized that the conformational abnormalities resulting in Z-AAT accumulation and consequent cellular response interfere with hepatocyte glycogen storage and/or metabolism, similar to other models of autophagy (26)(27)(28)(29). To assess this hypothesis, we evaluated a variety of glycogen-related metabolic parameters in PiZ transgenic mice.…”

supporting

confidence: 80%

“…0.5; Figure 2C). It is known that activity of acid a-glucosidase in lysosomes of hepatocytes is contributes to the glycogen degradation in the liver (26)(27)(28)(29). The liver of PiZ mice exhibited a mild but significant elevation in enzyme activity relative to wild-type mice (46% increase compared with mean wild-type level, P , 0.05; Figure 1D).…”

Section: Glycogen Metabolismmentioning

confidence: 93%

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Dysfunctional Glycogen Storage in a Mouse Model of α₁-Antitrypsin Deficiency

Hübner

Leopold

Kiuru

et al. 2009

Am J Respir Cell Mol Biol

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Autophagy is an intracellular pathway that contributes to the degradation and recycling of unfolded proteins. Based on the knowledge that autophagy affects glycogen metabolism and that a 1 -antitrypsin (AAT) deficiency is associated with an autophagic response in the liver, we hypothesized that the conformational abnormalities of the Z-AAT protein interfere with hepatocyte glycogen storage and/or metabolism. Compared with wild-type mice (WT), the Z-AAT mice had lower liver glycogen stores (P , 0.001) and abnormal activities of glycogen-related enzymes, including acid aglucosidase (P , 0.05) and the total glycogen synthase (P , 0.05). As metabolic consequences, PiZ mice demonstrated lower blood glucose levels (P , 0.05), lower body weights (P , 0.001), and lower fat pad weights (P , 0.001) compared with WT. After the stress of fasting or partial hepatectomy, PiZ mice had further reduced liver glycogen and lower blood glucose levels (both P , 0.05 compared WT). Finally, PiZ mice exhibited decreased survival after partial hepatectomy (P , 0.01 compared with WT), but this was normalized with postoperative dextrose supplementation. In conclusion, these observations are consistent with the general concept that abnormal protein conformation and degradation affects other cellular functions, suggesting that diseases in the liver might benefit from metabolic compensation if glycogen metabolism is affected.Keywords: autophagy; partial hepatectomy; fasting; glycogen degradation a 1 -Antitrypsin (AAT), a 52-kD, 394-amino acid single-chain glycoprotein produced primarily by liver hepatocytes, functions as the major circulating inhibitor of neutrophil elastase (1, 2). The common Z-AAT mutation (glu342lys, referred to as ''PiZ'', for ''protease inhibitor Z'') results in a systemic deficiency of AAT (1, 2). The consequences of this single amino acid substitution are profound, including emphysema secondary to deficiency of lung antielastase protection and cirrhosis resulting from the toxic effects of the accumulation of the abnormal Z-AAT molecules in the liver (1-5).The liver disease associated with AAT deficiency is a prototype of conformational diseases, disorders due to misfolding of proteins, with consequent aberrant intermolecular protein aggregation (2-7). In contrast to the normal M-type AAT, which rapidly transits through the endoplasmic reticulum (ER) and is efficiently secreted by hepatocytes, the Z-AAT form of AAT accumulates in the hepatocyte ER secondary to abnormal folding of the Z molecule, resulting in interaction between the reactive center loop of one Z-AAT molecule with the b-pleated sheet of a second, causing loop-sheet polymerization and consequent accumulation of Z-AAT in the ER (3, 4, 8-10).The understanding of the mechanism of the liver disease associated with AAT deficiency has been significantly advanced by studies of the ''PiZ'' mouse, a transgenic murine model of the Z form of AAT by Woo and colleagues (11, 12) and Perlmutter and colleagues (13)(14)(15)(16)(17)(18)(19). Recent studies demonstrated tha...

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confidence: 80%

Section: Glycogen Metabolismmentioning

confidence: 93%

Dysfunctional Glycogen Storage in a Mouse Model of α₁-Antitrypsin Deficiency

Hübner

Leopold

Kiuru

et al. 2009

Am J Respir Cell Mol Biol

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Behavior and histopathology as biomarkers for evaluation of the effects of paracetamol and propranolol in the neotropical fish species Phalloceros harpagos

Matus

Pereira

Silva-Zacarín

et al. 2018

Environ Sci Pollut Res

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Pharmaceutical drugs in the aquatic environment can induce adverse effects on nontarget organisms. This study aimed to assess the short-term effects of sublethal concentrations of both paracetamol and propranolol on the fish Phalloceros harpagos, specifically light/dark preference, swimming patterns, skin pigmentation, histopathology, and liver glycogen levels. Fish were acutely exposed to sublethal concentrations of both paracetamol (0.008, 0.08, 0.8, 8, 80 mg L) and propranolol (0.0001, 0.001, 0.01, 0.1, 1 mg L) under controlled conditions. For scototaxis, a significant preference for the dark compartment was observed for the group exposed to the highest concentration of paracetamol (80 mg L). Propranolol exposure significantly altered the swimming pattern, especially in fish exposed to the 0.001 mg L concentration. Pigmentation was reduced in propranolol-exposed fish (0.1, 1 mg L). The lowest concentration of propranolol (0.0001 mg L) induced a decrease of histochemical reaction for hepatic glycogen. These data demonstrate that pharmaceuticals can induce sublethal effects in nontarget organisms, even at low concentrations, compromising specific functions of the individual with ecological relevance, such as energy balance and behavior.

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