Abnormal Lipid and Glucose Metabolism in Obesity: Implications for Nonalcoholic Fatty Liver Disease

Parekh, Samir; Anania, Frank A.

doi:10.1053/j.gastro.2007.03.055

Cited by 297 publications

(248 citation statements)

References 157 publications

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“…Indeed, the expression of IL-6, one of the major STAT3-activating cytokines, is elevated in human liver diseases and HCC [52,53]. In addition, many HCC risk factors, including HCV infection and hepatosteatosis, cause oxidative stress [68][69][70] and just like JNK, STAT3 can also be activated in response to ROS accumulation [65]. As discussed below, NF-κB-induced expression of anti-oxidants prevents inadver- tent activation of STAT3 by ROS accumulation, but it needs to be determined whether NF-κB activity is downregulated during human hepatocarcinogenesis to allow STAT3 activation.…”

Section: Stat3 Signaling Is Turned On In Human Hccmentioning

confidence: 99%

NF-κB and STAT3 – key players in liver inflammation and cancer

2010

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Hepatocellular carcinoma (HCC), the major form of primary liver cancer, is one of the most deadly human cancers. The pathogenesis of HCC is frequently linked with continuous hepatocyte death, inflammatory cell infiltration and compensatory liver regeneration. Understanding the molecular signaling pathways driving or mediating these processes during liver tumorigenesis is important for the identification of novel therapeutic targets for this dreadful disease. The classical IKKβ-dependent NF-κB signaling pathway has been shown to promote hepatocyte survival in both developing and adult livers. In addition, it also plays a crucial role in liver inflammatory responses by controlling the expression of an array of growth factors and cytokines. One of these cytokines is IL-6, which is best known for its role in the liver acute phase response. IL-6 exerts many of its functions via activation of STAT3, a transcription factor found to be important for HCC development. This review will focus on recent studies on the roles of NF-κB and STAT3 in liver cancer. Interactions between the two pathways and their potential as therapeutic targets will also be discussed.

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Section: Stat3 Signaling Is Turned On In Human Hccmentioning

confidence: 99%

NF-κB and STAT3 – key players in liver inflammation and cancer

2010

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“…Fatty liver is frequently associated with local inflammation (steatohepatitis) and liver damage including advanced fibrosis and cirrhosis (22). Although the molecular mechanisms underlying fatty liver are not fully understood, dysregulation of lipid and glucose homeostasis caused by pathological conditions, such as increased systemic insulin resistance, reduced fatty acid oxidation, elevated hepatic fatty acid influx, and enhanced de novo lipogenesis, plays a crucial role in the development of fatty liver (23). Indeed, therapies aimed at reducing body weight and/or alleviating insulin resistance improve fatty liver (1,2).…”

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confidence: 99%

Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity

Kim

Lee

Hun

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

210

146

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AMP-activated protein kinase (AMPK) plays an important role in regulating whole body energy homeostasis. Recently, it has been demonstrated that berberine (BBR) exerts antiobesity and antidiabetic effects in obese and diabetic rodent models through the activation of AMPK in peripheral tissues. Here we show that BBR improves lipid dysregulation and fatty liver in obese mice through central and peripheral actions. In obese db/db and ob/ob mice, BBR treatment reduced liver weight, hepatic and plasma triglyceride, and cholesterol contents. In the liver and muscle of db/db mice, BBR promoted AMPK activity and fatty acid oxidation and changed expression of genes involved in lipid metabolism. Additionally, intracerebroventricular administration of BBR decreased the level of malonyl-CoA and stimulated the expression of fatty acid oxidation genes in skeletal muscle. Together, these data suggest that BBR would improve fatty liver in obese subjects, which is probably mediated not only by peripheral AMPK activation but also by neural signaling from the central nervous system.

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“…It is estimated that the prevalence of NAFLD in developed countries reaches 10% to 24% of the population 2 , depending on the diagnostic criteria used 3 , while the worldwide prevalence of NASH reaches 2% to 3% of the general population 3 . The difficulty in assessing the prevalence of NAFLD includes the absence of signs and symptoms, the low sensitivity of liver enzymes as indicators of the disease and the doubtful need of biopsy as gold standard for diagnosis 3 . The NAFLD can be defined as liver accumulation of lipids, primarily in the form of triglycerides, without ingestion of significant quantities of alcohol and with the exclusion of other known causes of steatosis, as some drugs and toxins 4 .…”

Section: Introductionmentioning

confidence: 99%

“…Electron microscopy revealed that in the presence of NAFLD, the mitochondria are larger and bulkier, less in number and the mitochondrial matrix has paracrystalline inclusion and lower density 14 . Moreover IR is considered as the most common risk factor for the development of NAFLD, and this one as a hepatic manifestation of the Metabolic Syndrome (MS), depending on the diagnostic criteria used 3 . Independently of weight gain, MS is a great predictor for NAFLD, so important that became recognized as the hepatic manifestation of this syndrome 8 , since the prevalence of MS reaches 34% in the U.S. population, 53% in individuals with NAFLD and more than 88% in those with NASH 15,16 .…”

Section: Introductionmentioning

confidence: 99%

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Fructose and NAFLD: metabolic implications and models of induction in rats

Castro¹,

Cardoso²,

Vannucchi³

et al. 2011

Acta Cir. Bras.

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PURPOSE:The increase in fructose consumption is paralleled by a higher incidence of obesity worldwide. This monosaccharide is linked to metabolic syndrome, being associated with hypertriglyceridemia, hypertension, insulin resistance and diabetes mellitus. It is metabolized principally in the liver, where it can be converted into fatty acids, which are stored in the form of triglycerides leading to NAFLD. Several models of NAFLD use diets high in simple carbohydrates. Thus, this study aimed to describe the major metabolic changes caused by excessive consumption of fructose in humans and animals and to present liver abnormalities resulting from high intakes of fructose in different periods of consumption and experimental designs in Wistar rats. METHODS: Two groups of rats were fasted for 48 hours and reefed for 24 or 48 hours with a diet containing 63% fructose. Another group of rats was fed an diet with 63% fructose for 90 days. RESULTS: Refeeding for 24 hours caused accumulation of large amounts of fat, compromising 100% of the hepatocytes. The amount of liver fat in animals refed for 48 hours decreased, remaining mostly in zone 2 (medium-zonal). In liver plates of Wistar rats fed 63% fructose for 45, 60 and 90 days it's possible to see that there is an increase in hepatocytes with fat accumulation according to the increased time; hepatic steatosis, however, is mild, compromising about 20% of the hepatocytes. CONCLUSIONS: Fructose is highly lipogenic, however the induction of chronic models in NAFLD requires long periods of treatment. The acute supply for 24 or 48 hours, fasted rats can cause big changes, liver steatosis with macrovesicular in all lobular zones. Key words: Fructose. Fatty Liver. Diet. Rats. RESUMO OBJETIVO:O aumento do consumo de frutose é concomitante a maior incidência mundial de obesidade. Este monossacarídeo está relacionado à Síndrome Metabólica, sendo vinculado à hipertrigliceridemia, hipertensão arterial, resistência à insulina e diabetes mellitus. É metabolizada principalmente no fígado, onde pode ser convertida em ácidos graxos, os quais serão estocados na forma de trigligérides ocasionando a esteatose hepática não alcoólica (NAFLD). Vários modelos de NAFLD utilizam dietas ricas em carboidratos simples. Desta forma, este trabalho teve como objetivos descrever as principais alterações metabólicas causadas pelo consumo excessivo de frutose em humanos e em animais e apresentar as alterações hepáticas decorrentes da alta ingestão de frutose em diferentes períodos de consumo e desenhos experimentais em ratos Wistar. MÉTODOS: Dois grupos de ratos Wistar foram mantidos em jejum durante 48 horas e realimentados por 24 ou 48 horas com dieta contendo 63% de frutose. Outro grupo de ratos Wistar foi alimentado com 63% de frutose durante 90 dias. RESULTADOS: A realimentação por 24 horas provocou acúmulo de grande quantidade de gordura. A quantidade de gordura hepática nos animais realimentados por 48 horas diminuiu, mantendo-se principalmente nas zona 2 (medio-zonal). Em fígados de ratos Wi...

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Abnormal Lipid and Glucose Metabolism in Obesity: Implications for Nonalcoholic Fatty Liver Disease

Cited by 297 publications

References 157 publications

NF-κB and STAT3 – key players in liver inflammation and cancer

NF-κB and STAT3 – key players in liver inflammation and cancer

Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity

Fructose and NAFLD: metabolic implications and models of induction in rats

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