Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease – novel insights into cellular communication circuits

Peiseler, Moritz; Schwabe, Robert F.; Hampe, Jochen; Kubes, Paul; Heikenwälder, Mathias; Tacke, Frank

doi:10.1016/j.jhep.2022.06.012

Cited by 248 publications

(187 citation statements)

References 292 publications

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“…Therefore, environmental cues triggered during liver injury can indeed drive hepatocellular dedifferentiation. These signals include cytokines, chemokines, growth factors and extracellular matrix proteins, and are mostly produced by inflammatory cells and other nonparenchymal cells such as activated stellate cells and sinusoidal endothelial cells [69,[129][130][131]. Biliary epithelial cells, which are quiescent under physiological conditions, also undergo profound modifications during liver injury, adopting a proliferative, secretory and ultimately sensecent phenotype.…”

Section: Loss Of Hepatic Function In Liver Diseasementioning

confidence: 99%

Loss of liver function in chronic liver disease: An identity crisis

Berasain¹,

Arechederra²,

Argemí³

et al. 2023

Journal of Hepatology

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Section: Loss Of Hepatic Function In Liver Diseasementioning

confidence: 99%

Loss of liver function in chronic liver disease: An identity crisis

Berasain¹,

Arechederra²,

Argemí³

et al. 2023

Journal of Hepatology

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“…Inflammation in NAFLD/NASH is regulated by the NF-κB signaling cascade, which can activate the transcription of genes encoding pro-inflammatory enzymes and mediators, such as iNOS, cytokines, and chemokines [ 4 , 9 , 30 , 41 ]. Pro-inflammatory mediators from stressed or dying liver cells, as well as immune cells, may promote the activation and infiltration of inflammatory cells into the liver, thereby damaging liver cells [ 4 , 42 , 43 ]. The activation of NF-κB by stress stimuli, such as ROS, also transactivates the expression of pro-oxidant enzymes (e.g., NOX), which, in turn, promote ROS production or oxidative stress and inflammation in the liver, thus favoring oxidative liver damage, such as lipoperoxidative damage, and eventually hepatocyte death [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

Red Rice Bran Extract Alleviates High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease and Dyslipidemia in Mice

et al. 2023

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Red rice bran extract (RRBE) is rich in phytonutrients and has been shown to have anti-diabetic, anti-inflammatory, and antioxidant properties. However, its anti-hepatic steatosis and anti-dyslipidemic properties have not been thoroughly investigated. This study examined the aforementioned properties of RRBE, the underlying mechanism by which it alleviated non-alcoholic fatty liver disease in high-fat diet (HFD)-fed mice, and its major bioactive constituents. The mice were divided into four groups based on their diet: (1) low-fat diet (LFD), (2) LFD with high-dose RRBE (1 g/kg/day), (3) HFD, and (4) HFD with three different doses of RRBE (0.25, 0.5, and 1 g/kg/day). The administration of RRBE, especially at medium and high doses, significantly mitigated HFD-induced hepatosteatosis and concomitantly improved the serum lipid profile. Further, RRBE modified the level of expression of lipid metabolism-related genes (adipose triglyceride lipase (ATGL), cluster of differentiation 36 (CD36), lipoprotein lipase (LPL), liver X receptor alpha (LXRα), sterol regulatory element-binding protein-1c (SREBP-1c), SREBP-2, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and carnitine palmitoyltransferase 1A (CPT1A)) in hepatic or adipose tissues and improved the expression of hepatic high-density lipoprotein cholesterol (HDL-C) metabolism-related genes (hepatic lipase (HL) and apolipoprotein A-ǀ (ApoA-ǀ)). RRBE also attenuated markers of liver injury, inflammation, and oxidative stress, accompanied by a modulated expression of inflammatory (nuclear factor-kappa B (NF-κB) and inducible nitric oxide synthase (iNOS)), pro-oxidant (p47phox), and apoptotic (B-cell lymphoma protein 2 (Bcl-2)-associated X and Bcl-2) genes in the liver. High-performance liquid chromatography analyses indicated the presence of protocatechuic acid, γ-oryzanol, vitamin E, and coenzyme Q10 in RRBE. Our data indicate that RRBE alleviates HFD-induced hepatosteatosis, dyslipidemia, and their pathologic complications in part by regulating the expression of key genes involved in lipid metabolism, inflammation, oxidative stress, and apoptosis.

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“…Larsson and Wolk ( Larsson and Wolk, 2007 ) found the risk of HCC increase by 17% in overweight people and 89% in people with obesity, indicating severity of metabolic imbalance is related to liver pathology. Several mechanisms have been identified that may link obesity to cancers such as HCC via abnormal hormone and cytokine action, exposure to metabolic toxicity, oxidative damage, dysregulated cell cycle, and impaired immunity ( Calle and Kaaks, 2004 ; Diehl and Day, 2017 ; Dyck and Lynch, 2018 ; Gan et al, 2018 ; Anstee et al, 2019 ; Hou et al, 2020 ; Peiseler et al, 2022 ). The common theme is chronic metabolic burdens that arise in obesity drive persistently high levels of stress in hepatocytes and other types of liver cells and alter immune responses of the developing and established tumor ( Buck et al, 2017 ; Diehl and Day, 2017 ; Hotamisligil, 2017 ; Dyck and Lynch, 2018 ).…”

Section: Obesity-linked Non-alcoholic Fatty Liver Disease and Hepatoc...mentioning

confidence: 99%

“…Disrupting this interaction underlie a cluster of obesity-linked diseases, including NAFLD ( Hotamisligil, 2017 ). In obesity, there is increased risk of metabolic insults resulting from insulin resistance, diabetes, gut dysbiosis, abnormal bile acid metabolism, and hepatic lipid accumulation which can trigger maladaptive immunological responses that cause further insult and stimulate fibrosis-promoting actions by stellate cells ( Ioannou, 2016 ; Diehl and Day, 2017 ; Schwabe et al, 2020 ; Peiseler et al, 2022 ). Over time, these insults can cause organelle dysfunction and gene mutations that lead to HCC.…”

Section: Immunometabolic Drivers: Focus On Reactive Oxygen Species An...mentioning

confidence: 99%

Immunometabolic factors contributing to obesity-linked hepatocellular carcinoma

Akl

Widenmaier

2023

Front. Cell Dev. Biol.

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Hepatocellular carcinoma (HCC) is a major public health concern that is promoted by obesity and associated liver complications. Onset and progression of HCC in obesity is a multifactorial process involving complex interactions between the metabolic and immune system, in which chronic liver damage resulting from metabolic and inflammatory insults trigger carcinogenesis-promoting gene mutations and tumor metabolism. Moreover, cell growth and proliferation of the cancerous cell, after initiation, requires interactions between various immunological and metabolic pathways that provide stress defense of the cancer cell as well as strategic cell death escape mechanisms. The heterogenic nature of HCC in addition to the various metabolic risk factors underlying HCC development have led researchers to focus on examining metabolic pathways that may contribute to HCC development. In obesity-linked HCC, oncogene-induced modifications and metabolic pathways have been identified to support anabolic demands of the growing HCC cells and combat the concomitant cell stress, coinciding with altered utilization of signaling pathways and metabolic fuels involved in glucose metabolism, macromolecule synthesis, stress defense, and redox homeostasis. In this review, we discuss metabolic insults that can underlie the transition from steatosis to steatohepatitis and from steatohepatitis to HCC as well as aberrantly regulated immunometabolic pathways that enable cancer cells to survive and proliferate in the tumor microenvironment. We also discuss therapeutic modalities targeted at HCC prevention and regression. A full understanding of HCC-associated immunometabolic changes in obesity may contribute to clinical treatments that effectively target cancer metabolism.

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Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease – novel insights into cellular communication circuits

Cited by 248 publications

References 292 publications

Loss of liver function in chronic liver disease: An identity crisis

Loss of liver function in chronic liver disease: An identity crisis

Red Rice Bran Extract Alleviates High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease and Dyslipidemia in Mice

Immunometabolic factors contributing to obesity-linked hepatocellular carcinoma

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