Impaired autophagy promotes bile acid-induced hepatic injury and accumulation of ubiquitinated proteins

Kim, Soojin; Han, Sang Youn; Yu, Kwang Sik; Han, Daewon; Ahn, Hyo-Ju; Jo, Jae-Eun; Kim, Jin‐Hoi; Shin, Jongdae; Park, Hwan‐Woo

doi:10.1016/j.bbrc.2017.11.202

Cited by 28 publications

(31 citation statements)

References 23 publications

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“…Our data is the first report that the bile acids, DCA and CA, induce an increase in UPS and autophagy components associated with muscle atrophy. These results are in agreement with a report that bile acids cause the degradation of bile acid transporter via UPS from ileum and impaired autophagy in the liver (Kim et al, 2018;Miyata et al, 2013). Thus, our results suggest that DCA and CA could be stimulating the protein breakdown in skeletal muscle and thus contributing to muscle wasting.…”

Section: Discussionsupporting

confidence: 94%

Cholic acid and deoxycholic acid induce skeletal muscle atrophy through a mechanism dependent on TGR5 receptor

Ábrigo

González

Aguirre

et al. 2020

Journal Cellular Physiology

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Skeletal muscle atrophy is characterized by the degradation of myofibrillar proteins, such as myosin heavy chain or troponin. An increase in the expression of two muscle-specific E3 ligases, atrogin-1 and MuRF-1, and oxidative stress are involved in muscle atrophy. Patients with chronic liver diseases (CLD) develop muscle wasting. Several bile acids increase in plasma during cholestatic CLD, among them, cholic acid (CA) and deoxycholic acid (DCA). The receptor for bile acids, TGR5, is expressed in healthy skeletal muscles. TGR5 is involved in the regulation of muscle differentiation and metabolic changes. In this paper, we evaluated the participation of DCA and CA in the generation of an atrophic condition in myotubes and isolated fibers from the muscle extracted from wild-type (WT) and TGR5-deficient (TGR5 −/−) male mice. The results show that DCA and CA induce a decrease in diameter, and myosin heavy chain (MHC) protein levels, two typical atrophic features in C 2 C 12 myotubes. We also observed similar results when INT-777 agonists activated the TGR5 receptor. To evaluate the participation of TGR5 in muscle atrophy induced by DCA and CA, we used a culture of muscle fiber isolated from WT and TGR5 −/− mice.

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Section: Discussionsupporting

confidence: 94%

Cholic acid and deoxycholic acid induce skeletal muscle atrophy through a mechanism dependent on TGR5 receptor

Ábrigo

González

Aguirre

et al. 2020

Journal Cellular Physiology

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“…This notion was also supported by the accumulation of polyubiquitinylated proteins and ROS, which should have been regulated by autophagy and mitophagy (Fig. 5f) 34,35 . These sequential failures may lead to apoptosis-mediated cell death in cervical cancer cells.…”

Section: Discussionmentioning

confidence: 65%

Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins

Takeda

Komatsu²,

Chiwaki³

et al. 2019

Cell Death Dis

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Cervical cancer is the most common gynecological malignancy in the world; however, the survival rates of advanced-stage and recurrent cervical cancer patients remain poor. The multifaced protein insulin-like growth factor 2 receptor (IGF2R) has various ligands, represented as IGF-2 and mannose-6-phosphate (M6P)-tagged proteins. Regarding its antagonistic activity as an IGF1R signal, IGF2R is currently considered a tumor suppressor gene, whereas its significance as an M6P receptor is still unclear. Here, on the basis of transcriptome analysis of TCGA and GEO open datasets, we show that IGF2R is upregulated and correlated with poor prognosis in cervical cancer. Several experiments using cervical cancer cell lines revealed that IGF2R depletion induced apoptosis, decreased cell viability, and increased vulnerability to certain anticancer drug cisplatin. In contrast to its negligible impact in IGF1R signaling, loss of IGF2R disrupted the Golgi-to-lysosome transport of M6P-tagged cathepsins, resulting in decreased lysosomal activity, with their abnormal accumulation and dysfunction of both autophagy and mitophagy, which cause the accumulation of misfolded proteins and production of reactive oxygen species. Taken together, IGF2R has an oncogenic role through transportation of M6P-tagged cargo in cervical cancer and can be used as a predictive biomarker for prognostic classification.

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“…23 In contrast, several others found increased accumulation of ubiquitinated proteins and p62 in bile ductligated mice and concluded that autophagy and protein degradation was actually impaired in cholestasis. 5,6,24 In addition, mice with defective autophagy (i.e. Atg7 and Atg5 knockout mice or chloroquine inhibition of autophagy) have increased cholestatic liver injury.…”

Section: Discussionmentioning

confidence: 99%

FXR-dependent Rubicon induction impairs autophagy in models of human cholestasis

Panzitt

Jungwirth

Krones

et al. 2020

Journal of Hepatology

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In models of cholestasis, autophagy is impaired at late levels, when autophagosomes and lysosomes would normally fuse.The impairment depends on bile acids and FXRdependent induction of Rubicon.OCA impairs autophagy, while UDCA is a potent activator of hepatic autophagy. Autophagy, and in particular Rubicon, represents a novel molecular drug target in cholestatic liver diseases.UDCA may already be used in liver diseases where induction of autophagy is warranted.

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Impaired autophagy promotes bile acid-induced hepatic injury and accumulation of ubiquitinated proteins

Cited by 28 publications

References 23 publications

Cholic acid and deoxycholic acid induce skeletal muscle atrophy through a mechanism dependent on TGR5 receptor

Cholic acid and deoxycholic acid induce skeletal muscle atrophy through a mechanism dependent on TGR5 receptor

Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins

FXR-dependent Rubicon induction impairs autophagy in models of human cholestasis

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