Mammalian target of the rapamycin pathway is involved in non-alcoholic fatty liver disease

Wang, Yugang; Shi, Min; Fu, Hongyi; Xu, Hui; Wei, Jue; Wang, Ting; Wang, Xinmin

doi:10.3892/mmr.2010.365

Cited by 20 publications

(16 citation statements)

References 22 publications

(24 reference statements)

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“…When we analyzed these data using Ingenuity Pathway Analysis, several of the top pathways were linked to mTOR signaling (Table ). We found this intriguing, as although few reports have linked mTOR signaling directly to hepatic steatosis, mTOR signaling seemed an interesting pathway for steatosis and NASH, as mTOR clearly has an important role in several processes regulating cell growth and metabolism such as lipogenesis, protein translation, and autophagy . This led us to investigate the role of mTOR and Torc1 in our fructose‐induced model of hepatic steatosis in zebrafish larvae.…”

Section: Resultsmentioning

confidence: 85%

Fructose leads to hepatic steatosis in zebrafish that is reversed by mechanistic target of rapamycin (mTOR) inhibition

et al. 2014

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Nonalcoholic fatty liver disease (NAFLD), the accumulation of lipid within hepatocytes, is increasing in prevalence. Increasing fructose consumption correlates with this increased prevalence, and rodent studies directly support fructose leading to NAFLD. The mechanisms of NAFLD and in particular fructose-induced lipid accumulation remain unclear, although there is evidence for a role for endoplasmic reticulum (ER) stress and oxidative stress. We have evidence that NAFLD models demonstrate activation of the target of rapamycin complex 1 (Torc1) pathway. We set out to assess the contribution of ER stress, oxidative stress, and Torc1 up-regulation in the development of steatohepatitis in fructose-treated larval zebrafish. Zebrafish were treated with fructose or glucose as a calorie-matched control. We also treated larvae with rapamycin, tunicamycin (ER stress), or valinomycin (oxidative stress). Fish were stained with oil red O to assess hepatic lipid accumulation, and we also performed quantitative polymerase chain reaction (qPCR)and western blot analysis. We performed immunostaining on samples from patients with NAFLD and nonalcoholic steatohepatitis (NASH). Treatment with fructose induced hepatic lipid accumulation, mitochondrial abnormalities, and ER defects. In addition, fructose-treated fish showed activation of inflammatory and lipogenic genes. Treatment with tunicamycin or valinomycin also induced hepatic lipid accumulation. Expression microarray studies of zebrafish NAFLD models showed an elevation of genes downstream of Torc1 signaling. Rapamycin treatment of fructose-treated fish prevented development of hepatic steatosis, as did treatment of tunicamycin-or valinomycin-treated fish. Examination of liver samples from patients with hepatic steatosis demonstrated activation of Torc1 signaling. Conclusion: Fructose treatment of larval zebrafish induces hepatic lipid accumulation, inflammation, and oxidative stress. Our results indicate that Torc1 activation is required for hepatic lipid accumulation across models of NAFLD, and in patients. (HEPATOLOGY 2014;60:1581-1592

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Section: Resultsmentioning

confidence: 85%

Fructose leads to hepatic steatosis in zebrafish that is reversed by mechanistic target of rapamycin (mTOR) inhibition

et al. 2014

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“…Treating the mice with 3-maleimidopropionic acid or silencing the ATG5 gene with siRNA sharply increased the accumulation of lipid droplets in liver cells. Furthermore, rapamycin (mTOR inhibitor) was found to promote autophagy and also to alleviate lipid deposition both in vivo and in vitro [31]. Pretreatment with rapamycin (25 ng/mL) resulted in increased autophagy, while the levels of ER stress, apoptosis and lipid droplets decreased in palmitic acid-induced fatty hepatocytes[32].…”

Section: Nafld and Autophagymentioning

confidence: 99%

Traditional Chinese herbal extracts inducing autophagy as a novel approach in therapy of nonalcoholic fatty liver disease

Liu¹,

Liao²,

Li³

2017

WJG

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Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver diseases around the world due to the modern sedentary and food-abundant lifestyle, which is characterized by excessive fat accumulation in the liver related with causes other than alcohol abuse. It is widely acknowledged that insulin resistance, dysfunctional lipid metabolism, endoplasmic reticulum stress, oxidative stress, inflammation, and apoptosis/necrosis may all contribute to NAFLD. Autophagy is a protective self-digestion of intracellular organelles, including lipid droplets (lipophagy), in response to stress to maintain homeostasis. Lipophagy is another pathway for lipid degradation besides lipolysis. It is reported that impaired autophagy also contributes to NAFLD. Some studies have suggested that the histological characteristics of NAFLD (steatosis, lobular inflammation, and peri-sinusoid fibrosis) might be improved by treatment with traditional Chinese herbal extracts, while autophagy may be induced. This review will provide insights into the characteristics of autophagy in NAFLD and the related role/mechanisms of autophagy induced by traditional Chinese herbal extracts such as resveratrol, Lycium barbarum polysaccharides, dioscin, bergamot polyphenol fraction, capsaicin, and garlic-derived S-allylmercaptocysteine, which may inhibit the progression of NAFLD. Regulation of autophagy/lipophagy with traditional Chinese herbal extracts may be a novel approach for treating NAFLD, and the molecular mechanisms should be elucidated further in the near future.

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“…In addition, decreased activity of liver S6K1 [94], IKK β , and JNK1 [95] improves hepatic insulin sensitivity. Reciprocally, S6K1 activation in fat-fed mouse liver or specific activation of hepatic ERK1 by C-reactive protein is linked to steatosis and insulin resistance [96, 97]. These stress kinases are targets of PP2A [98–100], a redox-sensitive protein phosphatase inactivated in an oxidized environment.…”

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confidence: 99%

An Intimate Relationship between ROS and Insulin Signalling: Implications for Antioxidant Treatment of Fatty Liver Disease

Besse-Patin

Estall

2014

International Journal of Cell Biology

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Oxidative stress damages multiple cellular components including DNA, lipids, and proteins and has been linked to pathological alterations in nonalcoholic fatty liver disease (NAFLD). Reactive oxygen species (ROS) emission, resulting from nutrient overload and mitochondrial dysfunction, is thought to be a principal mediator in NAFLD progression, particularly toward the development of hepatic insulin resistance. In the context of insulin signalling, ROS has a dual role, as both a facilitator and inhibitor of the insulin signalling cascade. ROS mediate these effects through redox modifications of cysteine residues affecting phosphatase enzyme activity, stress-sensitive kinases, and metabolic sensors. This review highlights the intricate relationship between redox-sensitive proteins and insulin signalling in the context of fatty liver disease, and to a larger extent, the importance of reactive oxygen species as primary signalling molecules in metabolically active cells.

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Mammalian target of the rapamycin pathway is involved in non-alcoholic fatty liver disease

Cited by 20 publications

References 22 publications

Fructose leads to hepatic steatosis in zebrafish that is reversed by mechanistic target of rapamycin (mTOR) inhibition

Fructose leads to hepatic steatosis in zebrafish that is reversed by mechanistic target of rapamycin (mTOR) inhibition

Traditional Chinese herbal extracts inducing autophagy as a novel approach in therapy of nonalcoholic fatty liver disease

An Intimate Relationship between ROS and Insulin Signalling: Implications for Antioxidant Treatment of Fatty Liver Disease

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