Mitochondrial Dysfunction in the Transition from NASH to HCC

Léveillé, Mélissa; Estall, Jennifer L.

doi:10.3390/metabo9100233

Cited by 67 publications

(46 citation statements)

References 268 publications

(309 reference statements)

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“…Mitochondrial alterations are considered to be critical factors causing NAFLD and are thought to play an important role in promoting steatosis, inflammation, and progression to fibrosis [48,49]. Mitochondrial dysfunction can lead to an increased generation of reactive oxygen species (ROS) that could potentiate the effects of oxidative stress through the oxidization of polyunsaturated fatty acids, leading to the productions of aldehyde byproducts such as 4-hydroxynonenal (4-HNE; increased levels were confirmed in our study) and malondialdehyde (MDA) and also trigger pro-inflammatory cytokines ( [50] and references therein).…”

Section: Discussionsupporting

confidence: 60%

A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology

Hoek

Verschuren

Worms

et al. 2020

Cells

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Non-alcoholic steatohepatitis (NASH) is a fast-growing liver disorder that is associated with an increased incidence of cardiovascular disease and type 2 diabetes. Animal models adequately mimicking this condition are scarce. We herein investigate whether Ldlr−/−. Leiden mice on different high-fat diets represent a suitable NASH model. Ldlr−/−. Leiden mice were fed a healthy chow diet or fed a high-fat diet (HFD) containing lard or a fast food diet (FFD) containing milk fat. Additionally, the response to treatment with obeticholic acid (OCA) was evaluated. Both high-fat diets induced obesity, hyperlipidemia, hyperinsulinemia, and increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Mice on both diets developed progressive macro- and microvesicular steatosis, hepatic inflammation, and fibrosis, along with atherosclerosis. HFD induced more severe hyperinsulinemia, while FFD induced more severe hepatic inflammation with advanced (F3) bridging fibrosis, as well as more severe atherosclerosis. OCA treatment significantly reduced hepatic inflammation and fibrosis, and it did not affect atherosclerosis. Hepatic transcriptome analysis was compared with human NASH and illustrated similarity. The present study defines a translational model of NASH with progressive liver fibrosis and simultaneous atherosclerosis development. By adaptation of the fat content of the diet, either insulin resistance (HFD) or hepatic inflammation and fibrosis (FFD) can be aggravated.

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Section: Discussionsupporting

confidence: 60%

A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology

Hoek

Verschuren

Worms

et al. 2020

Cells

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“…Another interesting mechanism of MSCs is through transfer of mitochondria as reported in several previous studies [ 73 , 74 ]. Mitochondria have been considered a key player involved in many biologic processes in health and disease, including in HCC [ 75 , 76 , 77 , 78 , 79 ]. Some proinflammatory cytokines such as Il-6 and TNF-α can induce MSCs skeletal rearrangement and form tunneling nanotubes (TNT) through which mitochondria mobility occurs from MSCs to neighbor cells [ 73 , 80 ].…”

Section: Mesenchymal Stem Cells (Mscs)mentioning

confidence: 99%

Melatonin and Mesenchymal Stem Cells as a Key for Functional Integrity for Liver Cancer Treatment

Elmahallawy

Mohamed

Abdo

et al. 2020

IJMS

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Hepatocellular carcinoma (HCC) is the most common hepatobiliary malignancy with limited therapeutic options. On the other hand, melatonin is an indoleamine that modulates a variety of potential therapeutic effects. In addition to its important role in the regulation of sleep–wake rhythms, several previous studies linked the biologic effects of melatonin to various substantial endocrine, neural, immune and antioxidant functions, among others. Furthermore, the effects of melatonin could be influenced through receptor dependent and receptor independent manner. Among the other numerous physiological and therapeutic effects of melatonin, controlling the survival and differentiation of mesenchymal stem cells (MSCs) has been recently discussed. Given its controversial interaction, several previous reports revealed the therapeutic potential of MSCs in controlling the hepatocellular carcinoma (HCC). Taken together, the intention of the present review is to highlight the effects of melatonin and mesenchymal stem cells as a key for functional integrity for liver cancer treatment. We hope to provide solid piece of information that may be helpful in designing novel drug targets to control HCC.

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“…At the cellular level, liver damage through fat accumulation induces mitochondrial dysfunction, which can cause harmful effects on hepatic inflammation, reactive oxygen species (ROS) homeostasis, and cell death, resulting in NASH [ 12 ]. Simultaneously, it activates hepatic stellate cells (HSC) via progressive release of pro-inflammatory cytokines (platelet derived growth factor (PDGF), transforming growth factors-β (TGF-β), interleukin (IL)-1, tumor necrosis factor-α (TNF-α), and some chemokines) [ 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Pharmaceutical Efficacy of Gypenoside LXXV on Non-Alcoholic Steatohepatitis (NASH)

Lee¹,

Kim

et al. 2020

Biomolecules

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Ginsenosides have offered a wide array of beneficial roles in the pharmacological regulation of hepatic metabolic syndromes, including non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and obesity. Of the numerous ginsenosides, Rg3 has been widely investigated, but there have been few studies of gypenosides (Gyp). Particularly, no study on Gyp LXXV has been reported to date. Here, to firstly explore the pharmacological effects of Gyp LXXV against NASH and the related mechanism, methionine- and choline-deficient (MCD) diet-induced NASH mice and hepatic cells (stellate cells, hepatic macrophages, and hepatocytes) were selected. Gyp LXXV exhibited markedly alleviated MCD diet-induced hepatic injury, inflammation, and fibrosis by down-regulating hepatic fibrosis markers such as α-smooth muscle actin(α-SMA), collagen1, transforming growth factors-β (TGF-β1), tumor necrosis factor-α (TNF-α), MCP-1, interleukin (IL)-1β, nuclear factor κB (NFκB), and GRP78. Remarkably, histopathological studies confirmed that 15 mg/kg of Gyp LXXV administration to MCD diet-induced mice led to effective prevention of liver injury, lipid accumulation, and activation of hepatic macrophages, indicating that Gyp LXXV might be a potential anti-NASH drug.

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Mitochondrial Dysfunction in the Transition from NASH to HCC

Cited by 67 publications

References 268 publications

A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology

A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology

Melatonin and Mesenchymal Stem Cells as a Key for Functional Integrity for Liver Cancer Treatment

Pharmaceutical Efficacy of Gypenoside LXXV on Non-Alcoholic Steatohepatitis (NASH)

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