Aqueous Extract of Pepino Leaves Ameliorates Palmitic Acid-Induced Hepatocellular Lipotoxicity via Inhibition of Endoplasmic Reticulum Stress and Apoptosis

Hsu, Jen-Ying; Lin, Hui-Hsuan; Chyau, Charng-Cherng; Wang, Zhihong; Chen, Jing-Hsien

doi:10.3390/antiox10060903

Cited by 15 publications

(9 citation statements)

References 53 publications

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“…Flavanols (PB2, EPI, and CAT) were the most effective compounds in CAE, whereas TH and PCA showed similar effects as FGF21. Since PA can induce cell damage and apoptosis [ 51 ], treatments for preventing these effects can be considered for avoiding lipotoxicity-driven hepatosteatosis and NAFLD progression to non-alcoholic steatohepatitis (NASH) [ 52 ] ( Figure 2 H). In conjunction with hepatic steatosis, an inflammatory response occurs in hepatocytes in NAFLD conditions needing to be repressed [ 53 ].…”

Section: Resultsmentioning

confidence: 99%

Phytochemicals from the Cocoa Shell Modulate Mitochondrial Function, Lipid and Glucose Metabolism in Hepatocytes via Activation of FGF21/ERK, AKT, and mTOR Pathways

et al. 2022

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The cocoa shell is a by-product that may be revalorized as a source of bioactive compounds to prevent chronic cardiometabolic diseases. This study aimed to investigate the phytochemicals from the cocoa shell as targeted compounds for activating fibroblast growth factor 21 (FGF21) signaling and regulating non-alcoholic fatty liver disease (NAFLD)-related biomarkers linked to oxidative stress, mitochondrial function, and metabolism in hepatocytes. HepG2 cells treated with palmitic acid (PA, 500 µmol L−1) were used in an NAFLD cell model. Phytochemicals from the cocoa shell (50 µmol L−1) and an aqueous extract (CAE, 100 µg mL−1) enhanced ERK1/2 phosphorylation (1.7- to 3.3-fold) and FGF21 release (1.4- to 3.4-fold) via PPARα activation. Oxidative stress markers were reduced though Nrf-2 regulation. Mitochondrial function (mitochondrial respiration and ATP production) was protected by the PGC-1α pathway modulation. Cocoa shell phytochemicals reduced lipid accumulation (53–115%) and fatty acid synthase activity (59–93%) and prompted CPT-1 activity. Glucose uptake and glucokinase activity were enhanced, whereas glucose production and phosphoenolpyruvate carboxykinase activity were diminished. The increase in the phosphorylation of the insulin receptor, AKT, AMPKα, mTOR, and ERK1/2 conduced to the regulation of hepatic mitochondrial function and energy metabolism. For the first time, the cocoa shell phytochemicals are proved to modulate FGF21 signaling. Results demonstrate the in vitro preventive effect of the phytochemicals from the cocoa shell on NAFLD.

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Section: Resultsmentioning

confidence: 99%

Phytochemicals from the Cocoa Shell Modulate Mitochondrial Function, Lipid and Glucose Metabolism in Hepatocytes via Activation of FGF21/ERK, AKT, and mTOR Pathways

et al. 2022

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“…Nonetheless, CGA, KMP, and CHE exhibited the most effective results, while the phenolic acids, CA, PCA, and GA, demonstrated similar effects to FGF21. Considering that PA can induce cell damage and apoptosis ( 48 ), there is a need for dietary and nutraceutical-based treatments for preventing these effects and avoiding hepatic steatosis and the evolution of NAFLD into non-alcoholic steatohepatitis (NASH) ( Figure 4H ) ( 49 ). Besides hepatosteatosis, the inflammatory signaling cascade occurring in the liver cells under the NAFLD microenvironment must be suppressed ( 50 ).…”

Section: Resultsmentioning

confidence: 99%

Activating Effects of the Bioactive Compounds From Coffee By-Products on FGF21 Signaling Modulate Hepatic Mitochondrial Bioenergetics and Energy Metabolism in vitro

et al. 2022

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Coffee by-products contain bioactive compounds that have been shown to have the capacity to modulate human metabolism. The goal of this study was to investigate the effects of the main bioactive compounds in coffee by-products and two aqueous extracts from the coffee husk and silverskin on the activation of fibroblast growth factor 21 (FGF21) signaling and the subsequent regulation of mitochondrial bioenergetics and lipid and glucose metabolism. HepG2 cells treated with palmitic acid (PA) were used in a non-alcoholic fatty liver disease (NAFLD) cell model. The bioactive compounds from coffee by-products (50 μmol L−1) and the aqueous extracts from the coffee silverskin and coffee husk (100 μg mL−1) increased ERK1/2 phosphorylation and the secretion of FGF21 (1.3 to 1.9-fold). Coffee by-products' bioactive compounds counteracted inflammation and PA-triggered lipotoxicity. Oxidative stress markers (ROS, mitochondrial superoxide, and NADPH oxidase) and the activity of antioxidant enzymes (superoxide dismutase and catalase) were modulated through the activation of Nrf2 signaling. Mitochondrial bioenergetics were regulated by enhancing respiration and ATP production via PGC-1α, and the expression of oxidative phosphorylation complexes increased. Coffee by-products' bioactive compounds decreased lipid accumulation (23–41%) and fatty acid synthase activity (32–65%) and triggered carnitine palmitoyltransferase-1 activity (1.3 to 1.7-fold) by activating AMPK and SREBP-1c pathways. The GLUT2 expression and glucose uptake were increased (58–111%), followed by a promoted glucokinase activity (55–122%), while glucose production and phosphoenolpyruvate carboxykinase activity were reduced due to IRS-1/Akt1 regulation. The bioactive compounds from coffee by-products, primarily chlorogenic and protocatechuic acids, could regulate hepatic mitochondrial function and lipid and glucose metabolism by activating FGF21 and related signaling cascades.

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“…The aqueous extract from the leaves of the fruit Pepino ( Solanum muricatum Ait.) also alleviated the ER stress in HepG2 hepatocytes that were induced by lipotoxicity due to palmitic acid treatment, which is known to contribute to NAFLD development 168 . This aqueous extract was shown to decrease GRP78 and IRE1α phosphorylation levels and increase PERK levels, which were elevated and lowered, respectively, in palmitic acid‐treated cells compared to controls 169 .…”

Section: Implications For Nafld Treatmentmentioning

confidence: 89%

“…also alleviated the ER stress in HepG2 hepatocytes that were induced by lipotoxicity due to palmitic acid treatment, which is known to contribute to NAFLD development. 168 This aqueous extract was shown to decrease GRP78 and IRE1α phosphorylation levels and increase PERK levels, which were elevated and lowered, respectively, in palmitic acid-treated cells compared to controls. 169 Furthermore, while in palmitic acid-treated cells SREBP-1 and Nrf2 levels were reduced and Nrf2 was abnormally translocated to the nucleus, this aqueous extract of Pepino leaves increased SREBP-1 and Nrf2 protein levels, whilst it also enhanced the cytoplasmic Nrf2 translocation.…”

Section: Implications For Nafld Treatmentmentioning

confidence: 90%

Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD)

Flessa

Kyrou

Nasiri-Ansari

et al. 2022

J of Cellular Biochemistry

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Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of excessive alcohol consumption and is strongly associated with obesity, type 2 diabetes (T2DM) and other metabolic syndrome features. NAFLD is becoming increasingly prevalent and currently constitutes the leading cause of hepatocellular carcinoma (HCC). Recently, the term metabolic (dysfunction) associated fatty liver disease (MAFLD) has been proposed reflecting more accurately the underlying pathogenesis and the cardiometabolic disorders associated to NAFLD/MAFLD. Given the vital metabolic functions of the liver to maintain the body homeostasis, an extended endoplasmic reticulum (ER) network is mandatory in hepatocytes to retain its capacity to adapt to the multiple extracellular and intracellular signals mediating metabolic changes. Dysfunction of hepatocyte ER homeostasis and disturbance of its interaction with mitochondria have been recognized to be involved in the NAFLD pathophysiology. Apart from hepatocytes, hepatic stellate cells, and Kupffer cells have been shown to play an important role in the occurrence of NAFLD and progression to nonalcoholic steatohepatitis (NASH) with possibly different roles in the different stages of the NAFLD spectrum. Furthermore, excess lipid accumulation in the liver causes lipotoxicity which interacts with ER stress and culminates in inflammation and hepatocellular damage, mechanisms crucially implicated in NASH pathogenesis. Finally, the circadian clock machinery regulates ER stress‐related pathways and vice versa, thus controlling the homeostasis of the liver metabolism and being implicated in the NAFLD progression. This review presents a comprehensive overview of the current knowledge supporting the impact of ER stress signaling on NAFLD, whilst summarizing potential therapeutic interventions targeting this process.

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Aqueous Extract of Pepino Leaves Ameliorates Palmitic Acid-Induced Hepatocellular Lipotoxicity via Inhibition of Endoplasmic Reticulum Stress and Apoptosis

Cited by 15 publications

References 53 publications

Phytochemicals from the Cocoa Shell Modulate Mitochondrial Function, Lipid and Glucose Metabolism in Hepatocytes via Activation of FGF21/ERK, AKT, and mTOR Pathways

Phytochemicals from the Cocoa Shell Modulate Mitochondrial Function, Lipid and Glucose Metabolism in Hepatocytes via Activation of FGF21/ERK, AKT, and mTOR Pathways

Activating Effects of the Bioactive Compounds From Coffee By-Products on FGF21 Signaling Modulate Hepatic Mitochondrial Bioenergetics and Energy Metabolism in vitro

Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD)

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