Verapamil induces autophagy to improve liver regeneration in non-alcoholic fatty liver mice

Lai, Jianlin; Lian, Yuane; Wu, Junyi; Wang, Yaodong; Bai, Yan

doi:10.1080/21623945.2021.1983241

Cited by 11 publications

(11 citation statements)

References 35 publications

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“…All the mice used in this study were of C57BL/6 background and were raised at the Animal Experimental Center of Fujian Medical University under previously described conditions ( Lai et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

“…Mild and moderate liver fibrosis were set according to the proposed fibrosis staging criteria ( Zhao et al, 2008 ). Mice with moderate fibrosis were further intraperitoneally injected with verapamil (5 mg per kg bodyweight for 10 days) prior to 50% PHx for the induction of autophagy ( Lai et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

“…A plethora of evidence indicates that the depletion of the protein products of some critical autophagy-related genes, including Atg5 ( Toshima et al, 2014 ), Atg7 ( Lin et al, 2015 ; Romermann et al, 2020 ), and cathepsin L ( Sato et al, 2019 ), leads to impairment of hepatocyte mitosis and proliferation. By contrast, liver regeneration can be improved through stimulation of autophagic promoters ( Lin et al, 2015 ; Romermann et al, 2020 ; Lai et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Aberrant regulation of autophagy disturbs fibrotic liver regeneration after partial hepatectomy

Lian

Bai²,

Lai³

et al. 2022

Front. Cell Dev. Biol.

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Reports indicate that autophagy is essential for maintaining hepatocyte proliferative capacity during liver regeneration. However, the role of autophagy in fibrotic liver regeneration is incompletely elucidated. We investigated the deregulation of autophagic activities in liver regeneration after partial hepatectomy using a CCl4-induced fibrosis mouse model. The baseline autophagic activity was significantly increased in the fibrotic liver. After 50% partial hepatectomy (PHx), liver regeneration was remarkably decreased, accompanied by increased hepatocyte size and binuclearity ratio. Moreover, the expression of autophagy-related proteins was functionally deregulated and resulted in a reduction in the number of autophagosome and autophagosome–lysosome fusions. We further showed upregulation of autophagy activities through verapamil administration, improved hepatocyte proliferation capacity, and restricted cellular hypertrophy and binuclearity ratio. In conclusion, we demonstrated that the impairment of liver regeneration is associated with aberrant autophagy in fibrotic liver and that enhancing autophagy with verapamil may partially restore the impaired liver regeneration following PHx.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aberrant regulation of autophagy disturbs fibrotic liver regeneration after partial hepatectomy

Lian

Bai²,

Lai³

et al. 2022

Front. Cell Dev. Biol.

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“…Several Ca 2+ channel blockers, including fluspirilene, verapamil, loperamide, and amiodarone, have been found to induce autophagy potently 273,547–556 . Although the exact mechanisms are not clearly defined, there are reports indicating that the Ca 2+ channel antagonists‐induced autophagosome formation relates to calpain‐mediated cleavage of ATG5 273,552 …”

Section: Modulation Of Autophagy As Therapeutic Strategy In Human Dis...mentioning

confidence: 99%

“…539,540 Several Ca 2+ channel blockers, including fluspirilene, verapamil, loperamide, and amiodarone, have been found to induce autophagy potently. 273,[547][548][549][550][551][552][553][554][555][556] Although the exact mechanisms are not clearly defined, there are reports indicating that the Ca 2+ channel antagonists-induced autophagosome formation relates to calpain-mediated cleavage of ATG5. 273,552 Inositol monophosphatase (IMPase) inhibitors, including the approved mood-stabilizing agents, have been reported to perform neuroprotective activity via induction of autophagy.…”

Section: Other Autophagy Activatorsmentioning

confidence: 99%

Autophagy in health and disease: From molecular mechanisms to therapeutic target

Wang

Shi

et al. 2022

MedComm

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Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double‐membrane structure termed autophagosome and delivered to lysosome for degradation. Over the past two decades, autophagy has been extensively studied, from the molecular mechanisms, biological functions, implications in various human diseases, to development of autophagy‐related therapeutics. This review will focus on the latest development of autophagy research, covering molecular mechanisms in control of autophagosome biogenesis and autophagosome–lysosome fusion, and the upstream regulatory pathways including the AMPK and MTORC1 pathways. We will also provide a systematic discussion on the implication of autophagy in various human diseases, including cancer, neurodegenerative disorders (Alzheimer disease, Parkinson disease, Huntington's disease, and Amyotrophic lateral sclerosis), metabolic diseases (obesity and diabetes), viral infection especially SARS‐Cov‐2 and COVID‐19, cardiovascular diseases (cardiac ischemia/reperfusion and cardiomyopathy), and aging. Finally, we will also summarize the development of pharmacological agents that have therapeutic potential for clinical applications via targeting the autophagy pathway. It is believed that decades of hard work on autophagy research is eventually to bring real and tangible benefits for improvement of human health and control of human diseases.

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Increase in bile acids after sleeve gastrectomy improves metabolism by activating GPBAR1 to increase cAMP in mice with nonalcoholic fatty liver disease

Li,

Xu,

Chai

et al. 2024

Immunity Inflam & Disease

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BackgroundBile acids (BAs) concentration can affect metabolic improvement caused by bariatric surgery and BA concentrations increase in patients after sleeve gastrectomy (SG). Here, how BAs after SG affect metabolism in nonalcoholic fatty liver disease (NAFLD) was studied.MethodsMice were given high‐fat diet (HFD) to induce NAFLD and received SG surgery. Hepatic and fecal BA concentrations in mice were detected by liquid chromatography‐tandem mass spectrometry method. BA‐related genes were detected by quantitative real‐time polymerase chain reaction. G protein BA receptor 1 (GPBAR1) expression was identified using western blot analysis. NAFLD mice after SG received GPBAR1 inhibitor Triamterene. The weight of mice and mice liver was detected. Mouse liver tissue was observed by hematoxylin–eosin and Oil Red O staining. Triglyceride (TG), nonesterified fatty acid (NEFA), and cyclic adenosine monophosphate (cAMP) levels in mouse liver tissue were analyzed by metabolic assay and enzyme‐linked immune sorbent assay.ResultsSG boosted increase in hepatic total/conjugated BAs and related genes and GPBAR1 expression, and attenuated increase in fecal total BAs/muricholic acid in HFD‐induced mice and increased fecal taurine‐BAs in HFD‐induced mice. Triamterene (72 mg/kg) reversed the inhibitory role of SG in HFD‐induced increase of body weight, lipid accumulation, inflammatory cell infiltration, and increase of hepatic weight and TG/NEFA content, and counteracted the positive role of SG in HFD‐induced increase of hepatic cAMP concentration in mice.ConclusionsBAs improve metabolism via activating GPBAR1 to increase cAMP in NAFLD mice after SG.

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Verapamil induces autophagy to improve liver regeneration in non-alcoholic fatty liver mice

Cited by 11 publications

References 35 publications

Aberrant regulation of autophagy disturbs fibrotic liver regeneration after partial hepatectomy

Aberrant regulation of autophagy disturbs fibrotic liver regeneration after partial hepatectomy

Autophagy in health and disease: From molecular mechanisms to therapeutic target

Increase in bile acids after sleeve gastrectomy improves metabolism by activating GPBAR1 to increase cAMP in mice with nonalcoholic fatty liver disease

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