Free Fatty Acids Shift Insulin-induced Hepatocyte Proliferation towards CD95-dependent Apoptosis

Sommerfeld, Annika; Reinehr, Roland; Häussinger, Dieter

doi:10.1074/jbc.m114.617035

Cited by 19 publications

(8 citation statements)

References 56 publications

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“…**P < 0.01, ***P < 0.001 versus the control group; ##P < 0.01, ###P < 0.001 versus the HFD group. accumulation under the HFD and obesity conditions, leading to lipotoxic liver injury, which activates endoplasmic reticulum (ER) stress and mitochondrial dysfunction-dependent apoptotic signaling, resulting in hepatic apoptosis (29,30). In the present study, our data showed that HFD induced marked hepatic fat accumulation, augmented apoptosis-related protein levels and the percentages of hepatocytes undergoing apoptosis, indicating the occurrence of hepatic lipoapoptosis.…”

Section: Discussionsupporting

confidence: 51%

Purple sweet potato color protects against hepatocyte apoptosis through Sirt1 activation in high-fat-diet-treated mice

Su¹,

Zhang²,

Chen³

et al. 2020

Food & Nutrition Research

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Background: Recent evidence indicates that the inhibition of hepatocyte apoptosis is possible to develop a potential therapeutic strategy for nonalcoholic fatty liver disease (NAFLD). Our previous work suggested that purple sweet potato color (PSPC), a class of naturally occurring anthocyanins, effectively improved many features of high-fat diet (HFD)-induced NAFLD. However, whether PSPC ameliorates HFD-induced hepatocyte apoptosis has never been investigated. Objective: Here we investigated the effects of PSPC on HFD-induced hepatic apoptosis and the mechanisms underlying these effects. Design: Mice were divided into four groups: Control group, HFD group, HFD + PSPC group and PSPC group. PSPC was administered by daily oral gavage at doses of 700 mg/kg/day for 20 weeks. EX-527 (a SirT1-selective inhibitor) and Sirt1 siRNA were used to demonstrate the Sirt1 dependence of PSPC-mediated effects on apoptotic and survival signaling pathways in vivo and in vitro. Results: Our results showed that PSPC reduced body weights, hepatic triglyceride contents, histopathological lesions and serum ALT levels in a mouse model of NAFLD induced by HFD. Furthermore, PSPC attenuated HFD-induced hepatocyte apoptosis ratio from 7.27 ± 0.92% to 1.79 ± 0.27% in mouse livers, which is insignificant compared with that of controls. Moreover, PSPC activated Sirt1 by boosting NAD + level in HFD-treated mouse livers. Furthermore, PSPC promoted Sirt1-dependent suppression of P53-mediated apoptotic signaling and activation of Akt survival signaling pathway in HFD-treated mouse livers, which was confirmed by EX527 treatment. Moreover, Sirt1 knockdown abolished these ameliorative effects of PSPC on apoptosis and P53 acetylation and protein expression in PA-treated L02 cells. Ultimately, PSPC reduced Caspase-3 activation and Bax level, and elevated the Bcl-2 level in HFD-treated mouse livers. Conclusion: PSPC protected against HFD-induced hepatic apoptosis by promoting Sirt1-dependent inhibition of p53-apoptotic pathway and facilitation of Akt survival pathway. This study indicates that PSPC is a candidate for nutritional intervention of NAFLD.

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Section: Discussionsupporting

confidence: 51%

Purple sweet potato color protects against hepatocyte apoptosis through Sirt1 activation in high-fat-diet-treated mice

Su¹,

Zhang²,

Chen³

et al. 2020

Food & Nutrition Research

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“…Additionally, lipid accumulation triggers organelle dysfunction such as endoplasmic reticulum (ER) stress and oxidative stress, thereby triggering signaling cascades leading to apoptosis [14]. Likewise, free fatty acids can also interfere with insulin signaling, as well as activate death receptors leading to hepatocyte death [15]. …”

Section: Introductionmentioning

confidence: 99%

Role of cAMP and phosphodiesterase signaling in liver health and disease

Wahlang

McClain

Barve

et al. 2018

Cellular Signalling

108

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Liver disease is a significant health problem worldwide with mortality reaching around 2 million deaths a year. Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the major causes of chronic liver disease. Pathologically, NAFLD and ALD share similar patterns of hepatic disorders ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. It is becoming increasingly important to identify new pharmacological targets, given that there is no FDA-approved therapy yet for either NAFLD or ALD. Since the evolution of liver diseases is a multifactorial process, several mechanisms involving parenchymal and non-parenchymal hepatic cells contribute to the initiation and progression of liver pathologies. Moreover, certain protective molecular pathways become repressed during liver injury including signaling pathways such as the cyclic adenosine monophosphate (cAMP) pathway. cAMP, a key second messenger molecule, regulates various cellular functions including lipid metabolism, inflammation, cell differentiation and injury by affecting gene/protein expression and function. This review addresses the current understanding of the role of cAMP metabolism and consequent cAMP signaling pathway(s) in the context of liver health and disease. The cAMP pathway is extremely sophisticated and complex with specific cellular functions dictated by numerous factors such abundance, localization and degradation by phosphodiesterases (PDEs). Furthermore, because of the distinct yet divergent roles of both of its effector molecules, the cAMP pathway is extensively targeted in liver injury to modify its role from physiological to therapeutic, depending on the hepatic condition. This review also examines the behavior of the cAMP-dependent pathway in NAFLD, ALD and in other liver diseases and focuses on PDE inhibition as an excellent therapeutic target in these conditions.

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“…Adipose tissue insulin resistance is likely to play a significant role since it is related to increased liver damage [ 124 , 131 ]. The mechanisms might be mediated by an increased synthesis of saturated fatty acids, ceramides, phosphatidylcholines, monoacyl-, diacyl- and triacyl-glycerols (MAG, DAG and TAG) and downregulation of lysophosphocholine (LPC), causing mitochondrial dysfunction, oxidative injury and apoptosis by the elevation of lipid peroxides and free radicals [ 132 , 133 , 134 ].…”

Section: Lipotoxicity: Causes and Consequencesmentioning

confidence: 99%

The Subtle Balance between Lipolysis and Lipogenesis: A Critical Point in Metabolic Homeostasis

et al. 2015

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Excessive accumulation of lipids can lead to lipotoxicity, cell dysfunction and alteration in metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas and muscle. This is now a recognized risk factor for the development of metabolic disorders, such as obesity, diabetes, fatty liver disease (NAFLD), cardiovascular diseases (CVD) and hepatocellular carcinoma (HCC). The causes for lipotoxicity are not only a high fat diet but also excessive lipolysis, adipogenesis and adipose tissue insulin resistance. The aims of this review are to investigate the subtle balances that underlie lipolytic, lipogenic and oxidative pathways, to evaluate critical points and the complexities of these processes and to better understand which are the metabolic derangements resulting from their imbalance, such as type 2 diabetes and non alcoholic fatty liver disease.

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Free Fatty Acids Shift Insulin-induced Hepatocyte Proliferation towards CD95-dependent Apoptosis

Cited by 19 publications

References 56 publications

Purple sweet potato color protects against hepatocyte apoptosis through Sirt1 activation in high-fat-diet-treated mice

Purple sweet potato color protects against hepatocyte apoptosis through Sirt1 activation in high-fat-diet-treated mice

Role of cAMP and phosphodiesterase signaling in liver health and disease

The Subtle Balance between Lipolysis and Lipogenesis: A Critical Point in Metabolic Homeostasis

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