Involvement of the Autophagy-ER Stress Axis in High Fat/Carbohydrate Diet-Induced Nonalcoholic Fatty Liver Disease

Zhou, Xin; Fouda, Sherouk; Li, Dongli; Zhang, Kun; Ye, Ji-Ming

doi:10.3390/nu12092626

Cited by 16 publications

(14 citation statements)

References 67 publications

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“…Autophagy is an intracellular pathway that targets and delivers cellular components such as organelles and protein aggregates to lysosomes for degradation. Autophagy dysfunction has been identified as a key factor in the pathogenesis of several diseases, ranging from neurodegenerative disorders, such as Parkinson disease to metabolic disorders, such as nonalcoholic fatty liver disease (NAFLD) [ 1 , 2 , 3 ]. Indeed, many of the functions of autophagy are impaired in NAFLD, including its ability to regulate cellular insulin sensitivity, mediate hepatocyte resistance to harmful stimuli such as oxidants and cytokines, and metabolize cellular lipid stores by lipophagy [ 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells

et al. 2021

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Dietary flavonoids stimulate autophagy and prevent liver dysfunction, but the upstream signaling pathways triggered by these compounds are not well understood. Certain polyphenols bind directly to NRH-quinone oxidoreductase 2 (NQO2) and inhibit its activity. NQO2 is highly expressed in the liver, where it participates in quinone metabolism, but recent evidence indicates that it may also play a role in the regulation of oxidative stress and autophagy. Here, we addressed a potential role of NQO2 in autophagy induction by flavonoids. The pro-autophagic activity of seven flavonoid aglycons correlated perfectly with their ability to inhibit NQO2 activity, and flavones such as apigenin and luteolin showed the strongest activity in all assays. The silencing of NQO2 strongly reduced flavone-induced autophagic flux, although it increased basal LC3-II levels in HepG2 cells. Both flavones induced AMP kinase (AMPK) activation, while its reduction by AMPK beta (PRKAB1) silencing inhibited flavone-induced autophagy. Interestingly, the depletion of NQO2 levels by siRNA increased the basal AMPK phosphorylation but abrogated its further increase by apigenin. Thus, NQO2 contributes to the negative regulation of AMPK activity and autophagy, while its targeting by flavones releases pro-autophagic signals. These findings imply that NQO2 works as a flavone receptor mediating autophagy and may contribute to other hepatic effects of flavonoids.

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Section: Introductionmentioning

confidence: 99%

Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells

et al. 2021

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“…In addition, advanced glycation end products (AGE) can be a potential biomarker of the NAFLD stage since AGE showed good criteria for dividing patients with minimal steatosis (BARD score 0–1) vs. moderate steatosis (BARD score 2–4) [ 72 ]. Furthermore, a high intake of fat and carbohydrates can induce ER stress, and dysfunction of ER develops metabolically-driven NAFLD progress [ 73 , 74 ]. Although this study revealed that HCA had therapeutic effects by suppressing lipid accumulation and apoptosis in liver cells, other components may be effective to NAFLD since recent clinical trials suggest that protein oxidation/glycation and ER stress are involved in liver fibrosis in NAFLD [ 75 , 76 ].…”

Section: Discussionmentioning

confidence: 99%

Garcinia cambogia Ameliorates Non-Alcoholic Fatty Liver Disease by Inhibiting Oxidative Stress-Mediated Steatosis and Apoptosis through NRF2-ARE Activation

2021

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Excessive free fatty acids (FFAs) causes reactive oxygen species (ROS) generation and non-alcoholic fatty liver disease (NAFLD) development. Garcinia cambogia (G. cambogia ) is used as an anti-obesity supplement, and its protective potential against NAFLD has been investigated. This study aims to present the therapeutic effects of G. cambogia on NAFLD and reveal underlying mechanisms. High-fat diet (HFD)-fed mice were administered G. cambogia for eight weeks, and steatosis, apoptosis, and biochemical parameters were examined in vivo. FFA-induced HepG2 cells were treated with G. cambogia, and lipid accumulation, apoptosis, ROS level, and signal alterations were examined. The results showed that G. cambogia inhibited HFD-induced steatosis and apoptosis and abrogated abnormalities in serum chemistry. G. cambogia increased in NRF2 nuclear expression and activated antioxidant responsive element (ARE), causing induction of antioxidant gene expression. NRF2 activation inhibited FFA-induced ROS production, which suppressed lipogenic transcription factors, C/EBPα and PPARγ. Moreover, the ability of G. cambogia to inhibit ROS production suppressed apoptosis by normalizing the Bcl-2/BAX ratio and PARP cleavage. Lastly, these therapeutic effects of G. cambogia were due to hydroxycitric acid (HCA). These findings provide new insight into the mechanism by which G. cambogia regulates NAFLD progression.

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“…The steatosis itself does not pose a significant risk, but it can trigger inflammation that leads eventually to nonalcoholic steatohepatitis (NASH) and then to cellular injury and liver fibrosis (Lebeaupin et al, 2018; Zhou, Fouda, Li, Zhang, & Ye, 2020). Although the mechanisms behind NAFLD are not completely understood, ERS has been shown to play an important role in its pathogenesis (Song & Malhi, 2019; Zhou et al, 2020). The excess of lipids in cells heightens the level of oxidative stress that in turn disrupts protein folding leading to ERS (Fujii, Homma, Kobayashi, & Seo, 2018).…”

Section: Liver Diseasesmentioning

confidence: 99%

Resveratrol and endoplasmic reticulum stress: A review of the potential protective mechanisms of the polyphenol

Ahmadi

Hayes

Karimi

2021

Phytotherapy Research

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The endoplasmic reticulum (ER) is an organelle that performs a set of essential functions in cellular biology. These include synthesis of lipids, homeostasis of calcium, and controlling the folding of proteins. Inflammation and oxidative stress are two important reasons behind the accumulation of misfolded or unfolded proteins in the ER. In such circumstances, a series of measures are undertaken in the cell which are collectively called unfolded protein response (UPR). The aim of UPR is to reduce the burden of protein aggregates and promote survival. However, extended and unrestricted ER stress (ERS) can induce further inflammation and apoptosis. ERS and the UPR are involved in different diseases such as neurodegenerative and cardiovascular diseases.Resveratrol (RSV), a natural polyphenol, has well-documented evidence supporting its numerous biological properties including antioxidant, antiinflammatory, antiobesity, antidiabetic, and antiischemic activities. The compound is also known for its potential beneficial effects on cognitive function and liver, kidney, and lung health.In this review, the role of ERS in several pathological conditions and the potential protective effects of RSV are discussed. However, the scarcity of clinical data means that more research needs to be conducted to gain a lucid understanding of RSV's effects on endoplasmic reticulum stress (ERS) in humans.

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Involvement of the Autophagy-ER Stress Axis in High Fat/Carbohydrate Diet-Induced Nonalcoholic Fatty Liver Disease

Cited by 16 publications

References 67 publications

Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells

Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells

Garcinia cambogia Ameliorates Non-Alcoholic Fatty Liver Disease by Inhibiting Oxidative Stress-Mediated Steatosis and Apoptosis through NRF2-ARE Activation

Resveratrol and endoplasmic reticulum stress: A review of the potential protective mechanisms of the polyphenol

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