Regulation of hepatic cardiolipin metabolism by TNFα: Implication in cancer cachexia

Peyta, Laure; Jarnouen, Kathleen; Pinault, Michelle; Coulouarn, Cédric; Guimaraes, Cyrille; Goupille, Caroline; Barros, Jean‐Paul Pais de; Chevalier, Stéphan; Dumas, Jean‐François; Maillot, F.; Hatch, Grant M.; Loyer, Pascal; Servais, Stéphane

doi:10.1016/j.bbalip.2015.08.008

Cited by 29 publications

(28 citation statements)

References 48 publications

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“…All but two (GpGro 34:2, GpGro 38:4) contained ω3 or ω6 PUFA (Fig 11C); and all increased in livers of WD-fed mice. GpGro are cardiolipin precursors and cardiolipin is a major mitochondrial matrix phospholipid [87, 88]. Interestingly, increases in mitochondrial ω3 and ω6 PUFA is associated with increased generation of reactive oxygen species ( ROS ) and oxidative stress is linked to NAFLD [89].…”

Section: Resultsmentioning

confidence: 99%

Lipidomic and transcriptomic analysis of western diet-induced nonalcoholic steatohepatitis (NASH) in female Ldlr -/- mice

et al. 2019

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Background Nonalcoholic fatty liver disease ( NAFLD ) is the most common chronic liver disease worldwide, particularly in obese and type 2 diabetic individuals. NAFLD ranges in severity from benign steatosis to nonalcoholic steatohepatitis ( NASH ); and NASH can progress to cirrhosis, primary hepatocellular carcinoma ( HCC ) and liver failure. As such, NAFLD has emerged as a major public health concern. Herein, we used a lipidomic and transcriptomic approach to identify lipid markers associated with western diet ( WD ) induced NASH in female mice. Methods Female mice (low-density lipoprotein receptor null ( Ldlr -/- ) were fed a reference or WD diet for 38 and 46 weeks. Transcriptomic and lipidomic approaches, coupled with statistical analyses, were used to identify associations between major NASH markers and transcriptomic & lipidomic markers. Results The WD induced all major hallmarks of NASH in female Ldlr -/- mice, including steatosis (SFA, MUFA, MUFA-containing di- and triacylglycerols), inflammation ( TNFα) , oxidative stress (Ncf2) , and fibrosis (Col1A) . The WD also increased transcripts associated with membrane remodeling (LpCat) , apoptosis & autophagy ( Casp1 , CtsS ), hedgehog ( Taz ) & notch signaling ( Hey1 ), epithelial-mesenchymal transition (S1004A) and cancer ( Gpc3 ). WD feeding, however, suppressed the expression of the hedgehog inhibitory protein ( Hhip ), and enzymes involved in triglyceride catabolism ( Tgh/Ces3 , Ces1g) , as well as the hepatic abundance of C 18-22 PUFA-containing phosphoglycerolipids (GpCho, GpEtn, GpSer, GpIns). WD feeding also increased hepatic cyclooxygenase (Cox1 & 2) expression and pro-inflammatory ω6 PUFA-derived oxylipins (PGE2), as well as lipid markers of oxidative stress (8-iso-PGF2α). The WD suppressed the hepatic abundance of reparative oxylipins (19, 20-DiHDPA) as well as the expression of enzymes involved in fatty epoxide metabolism ( Cyp2C , Ephx ). Conclusion WD-induced NASH in female Ldlr -/ - mice was characterized by a massive increase in hepatic neutral and membrane lipids containing SFA and MUFA and a loss of C 18-22 PUFA-containing membrane lipids. Moreover, the WD increased hepatic pro-inflammatory oxylipins and suppressed the hepatic abundance of reparative o...

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Section: Resultsmentioning

confidence: 99%

Lipidomic and transcriptomic analysis of western diet-induced nonalcoholic steatohepatitis (NASH) in female Ldlr -/- mice

et al. 2019

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“…Energy wasting in the liver under cachectic conditions leads to a reduction in the oxidative phosphorylation capacity of mitochondria due to an increase in mitochondrial cardiolipin content . This is accompanied by an increase of TNFα resulting in enhanced expression of phosphatidylglycerolphosphate synthase , which mediates cardiolipin expression . In addition, decreased usage of hepatic triglyceride stores has been demonstrated in cancer cachexia, due to enhanced expression of the transcriptional cofactors RIP140 and TSC22D4 , leading to hepatic steatosis.…”

Section: Dysfunctional Peripheral Handling Of Energy Substratesmentioning

confidence: 99%

Energy metabolism in cachexia

et al. 2019

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Cachexia is a wasting disorder that accompanies many chronic diseases including cancer and results from an imbalance of energy requirements and energy uptake. In cancer cachexia, tumor‐secreted factors and/or tumor–host interactions cause this imbalance, leading to loss of adipose tissue and skeletal and cardiac muscle, which weakens the body. In this review, we discuss how energy enters the body and is utilized by the different organs, including the gut, liver, adipose tissue, and muscle, and how these organs contribute to the energy wasting observed in cachexia. We also discuss futile cycles both between the organs and within the cells, which are often used to fine‐tune energy supply under physiologic conditions. Ultimately, understanding the complex interplay of pathologic energy‐wasting circuits in cachexia can bring us closer to identifying effective treatment strategies for this devastating wasting disease.

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“…Furthermore, reduced ATP synthesis and elevated energy wasting have been reported in hepatocytes mitochondria of a mice model of peritoneal carcinosis. Cardiolipin, a protein essential to liver oxidative phosphorylation, has shown to be increased in the cachectic mice [102] and biosynthesis dysregulation of cardiolipin has been mediated by TNF in vitro [103]. In humans, steatosis in hepatocytes has been described in cachectic patients [104].…”

Section: Role Of Liver Cells In Metabolismmentioning

confidence: 99%

Cancer Cachexia and Related Metabolic Dysfunction

Fonseca

Farkaš

Dora

et al. 2020

IJMS

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Cancer cachexia is a complex multifactorial syndrome marked by a continuous depletion of skeletal muscle mass associated, in some cases, with a reduction in fat mass. It is irreversible by nutritional support alone and affects up to 74% of patients with cancer—dependent on the underlying type of cancer—and is associated with physical function impairment, reduced response to cancer-related therapy, and higher mortality. Organs, like muscle, adipose tissue, and liver, play an important role in the progression of cancer cachexia by exacerbating the pro- and anti-inflammatory response initially activated by the tumor and the immune system of the host. Moreover, this metabolic dysfunction is produced by alterations in glucose, lipids, and protein metabolism that, when maintained chronically, may lead to the loss of skeletal muscle and adipose tissue. Although a couple of drugs have yielded positive results in increasing lean body mass with limited impact on physical function, a single therapy has not lead to effective treatment of this condition. Therefore, a multimodal intervention, including pharmacological agents, nutritional support, and physical exercise, may be a reasonable approach for future studies to better understand and prevent the wasting of body compartments in patients with cancer cachexia.

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Regulation of hepatic cardiolipin metabolism by TNFα: Implication in cancer cachexia

Cited by 29 publications

References 48 publications

Lipidomic and transcriptomic analysis of western diet-induced nonalcoholic steatohepatitis (NASH) in female Ldlr -/- mice

Lipidomic and transcriptomic analysis of western diet-induced nonalcoholic steatohepatitis (NASH) in female Ldlr -/- mice

Energy metabolism in cachexia

Cancer Cachexia and Related Metabolic Dysfunction

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