Obesity-associated mechanisms of hepatocarcinogenesis

Karagozian, Raffi; Derdák, Zoltán; Baffy, György

doi:10.1016/j.metabol.2014.01.011

Cited by 150 publications

(126 citation statements)

References 144 publications

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“…In 2014, around 600 million people worldwide were estimated to be obese [2]. Obesity is associated with many common diseases, such as nonalcoholic fatty liver, hypertension, osteoarthritis, cardiovascular diseases, stroke, type 2 diabetes, and various cancers [3–6]. Due to the medical importance of obesity, considerable research has been devoted to developing appropriate treatments.…”

Section: Introductionmentioning

confidence: 99%

Polygala tenuifolia extract inhibits lipid accumulation in 3T3-L1 adipocytes and high-fat diet–induced obese mouse model and affects hepatic transcriptome and gut microbiota profiles

Wang

Yen

Cheng

et al. 2017

Food & Nutrition Research

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Obesity, the excessive accumulation of lipids in the body, is closely associated with many prevalent human disorders. Continued efforts to identify plant extracts that exhibit anti-obesity effects have drawn much attention. This study investigated whether a Polygala tenuifolia extract (PTE) possesses anti-obesity activity and how PTE may affect liver gene expression and gut microbiota. We used 3T3-L1 adipocytes and a high-fat diet–induced obese mouse model to determine the effects of PTE on lipid accumulation. Next-generation sequencing analysis of liver gene expression and gut microbiota profiles following PTE treatment were conducted to elucidate possible mechanisms. We found that treatment of fully differentiated 3T3-L1 adipocytes with PTE inhibited lipid accumulation in the cells through reducing lipid formation and triglyceride content and by increasing lipase activity. No cytotoxicity was observed from the PTE treatment. After 5 weeks of treatment with PTE, the increased body weight, elevated serum triglyceride content, and liver steatosis in the high-fat diet–induced obese mice were each reduced. Liver transcriptomic analysis revealed that expression of genes involved in lipid and cholesterol metabolism was significantly altered. The low-grade chronic inflammation of obesity caused by a high-fat diet was also decreased after PTE treatment. In addition, treatment with PTE improved the relatively low Bacteroidetes/Firmicutes ratio in the gut of high-fat diet–fed mice through enrichment of the Proteobacteria population and reduction of the Deferribacteres population. In conclusion, treatment with PTE inhibited lipid accumulation by inducing the expression of the master transcription factor PPARα, attenuated the low-grade chronic inflammation of obesity, and also altered gut microbiota profiles. These results indicate that PTE has the potential to be developed into an anti-obesity food supplement and therapy. Abbreviations: Abcg5: ATP-binding cassette subfamily G member 5; ALT: alanine aminotransferase; AMPK: adenosine monophosphate-activated protein kinase; AST: aspartate aminotransferase; B/F: Bacteroidetes to Firmicutes [ratio]; C/EBPα: CCAAT/enhancer-binding protein alpha; CR: creatinine; Cyp51: cytochrome P450 family 51; DMEM: Dulbecco’s modified Eagle’s medium; Fabp5: fatty acid-binding protein 5; FBS: fetal bovine serum; Fdps: farnesyl diphosphate synthase; Glc: Glucose; HFD: high-fat diet; GO: gene ontology; HPRT: hypoxanthine guanine phosphoribosyl transferase; IBMS: 3-isobutyl-1-methylxanthine; Idi1: isopentenyl-diphosphate delta isomerase 1; IL-1β: interleukin-1-beta; Lpin1: phosphatidic acid phosphohydrolase; LPS: lipopolysaccharide; Mvd: mevalonate diphosphate decarboxylase; ND: normal diet; OTU: operational taxonomic units; Pcsk9: proprotein convertase subtilisin/kexin 9; Pctp: phosphatidylcholine transfer protein; PPARα: peroxisome proliferator-activated receptor alpha; PPARγ: peroxisome proliferator-activated receptor gamma; PTE: Polygala tenuifolia extract; Saa1: serum amyloid A1; SD: ...

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Section: Introductionmentioning

confidence: 99%

Polygala tenuifolia extract inhibits lipid accumulation in 3T3-L1 adipocytes and high-fat diet–induced obese mouse model and affects hepatic transcriptome and gut microbiota profiles

Wang

Yen

Cheng

et al. 2017

Food & Nutrition Research

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“…On the other hand, there are multiple oncogenic mechanisms that participate in genomic instability: alterations in the DNA-damage-response pathways, telomere erosion, chromosome segregation defects [9] . Even if several pathogenic mechanisms, such as obesity-mediated chronic inflammation and diabetes, have been described to be involved in NAFLD related HCC till now, as extensively reported below, we do not have clear ideas on the pathogenic mechanisms driving transformation of the cell during NAFLD [10,11] . In this context, low grading chronic inflammation has indubitably a crucial role in NAFLD disease progression toward HCC [12] .…”

Section: Introductionmentioning

confidence: 93%

Fat and hepatocellular carcinoma

Balsano¹,

Porcu²,

Sideri³

et al. 2018

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Obesity and diabetes are associated with the onset of hepatocellular carcinoma (HCC). These two illnesses correlate also with the development of non-alcoholic fatty liver disease (NAFLD). Currently, NAFL is considered the leading form of chronic liver disease in the Western industrialized countries. Insulin resistance is the common pathogenic factor among these three pathologies. NAFL is characterized by fat accumulation in the liver that involves greater than 5% of the liver parenchyma with no evidence of hepatocyte injury. However, NAFL may progress toward non-alcoholic steatohepatitis that in turn may lead to advanced fibrosis, cirrhosis and HCC. It is alarming that NAFLD related HCC has been, at present, considered as a growing burden worldwide, and its prevalence is tending to further increase together with the increasing incidence of obesity and diabetes. Worthy of note is that in the presence of chronic accumulation of fat in the liver it has been reported the emergence of HCC during chronic liver disease in absence of liver cirrhosis, usually the major risk factor for the development of HCC. Thus, in the future NAFLD related HCCs will place a growing strain on health-care systems from the need for their management. Unfortunately, most of the NAFLD related HCC patients are diagnosed at advanced stages and are characterized by a poor prognosis, because they are ineligible to radical treatments. Thus, it is urgent to boost up new screening policies to make early diagnoses, as well as to develop preventive-therapeutic strategies.

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“…An increase in intrahepatic fat accumulation, a type of ectopic fat accumulation, causes systemic metabolic abnormalities in the body leading to the development of fatty liver, which may evolve into liver cirrhosis and liver cancer [4][5][6] . Although fatty liver tends to be comorbid with obesity or being over-weight, a considerable non-obese normal and under-weight population are known to have fatty liver and suffer from abnormalities in liver function and insulin resistance 7) .…”

Section: Intrahepatic Fat Accumulationmentioning

confidence: 99%

Protective effects of dietary restriction and physical exercise on intrahepatic fat accumulation

Kurosaka

Yamauchi

Takemori

et al. 2018

JPFSM

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This paper discusses the effects of dietary restriction and physical exercise on the maintenance of good health, focusing on intrahepatic fat accumulation, a type of ectopic fat accumulation. Excessive intrahepatic fat accumulation eventually progresses to fatty liver, which may evolve into liver cirrhosis and liver cancer. Physical exercise and dietary restriction are generally accepted as the major non-pharmacological remedies against intrahepatic fat accumulation. However, a combination of diet and physical activity has not necessarily shown expected synergistic or additive effects. In fact, dietary conditions antagonistically blocked the effect of physical activity on fatty liver, and physical inactivity adversely exacerbated the effect of dietary restriction on intrahepatic fat accumulation. These diverse combination effects, as well as etiology-dependent diversity in the activation of cellular signaling pathways leading to fatty liver, suggest the need to optimize remedies for the efficient amelioration and prevention of intrahepatic fat accumulation in a case-dependent manner. As a tentative step to constructing a prescription formula for optimal remedies, the probable advantage of physical exercise over dietary restriction at preventing fat spillover from adipose tissue to liver is noted.

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Obesity-associated mechanisms of hepatocarcinogenesis

Cited by 150 publications

References 144 publications

Polygala tenuifolia extract inhibits lipid accumulation in 3T3-L1 adipocytes and high-fat diet–induced obese mouse model and affects hepatic transcriptome and gut microbiota profiles

Polygala tenuifolia extract inhibits lipid accumulation in 3T3-L1 adipocytes and high-fat diet–induced obese mouse model and affects hepatic transcriptome and gut microbiota profiles

Fat and hepatocellular carcinoma

Protective effects of dietary restriction and physical exercise on intrahepatic fat accumulation

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