The hepatic circadian clock is preserved in a lipid-induced mouse model of non-alcoholic steatohepatitis

Ando, Hitoshi; Takamura, Toshinari; Nagata, Naoto; Shima, Kosuke R.; Nakamura, Seiji; Kumazaki, Masafumi; Kurita, Seiichiro; Makino, Hírofumi; Togawa, Naoyuki; Fukushima, Tamio; Fujimura, Akio; Kaneko, Shuichi

doi:10.1016/j.bbrc.2009.01.150

Cited by 24 publications

(14 citation statements)

References 40 publications

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“…Previously, we reported that the amount of ethanol-dependent triglyceride accumulation is dependent on the fat content of the diet suggesting an interaction between ethanol and fat [31]. However, daily oscillations of clock genes were shown to be maintained in the liver of mice fed a high-fat atherogenic diet (34.3% fat) for 5 wk, despite the presence of non-alcoholic steatohepatitis [32]. Studies using ethanol in drinking water typically show little to no hepatic steatosis with lower blood alcohol levels in the dark phase presumably due to metabolic tolerance [33], whereas in the current study blood alcohol levels in the dark phase (ZT15) were >300 mg/dL.…”

Section: Discussionmentioning

confidence: 92%

Chronic Ethanol Consumption Disrupts the Core Molecular Clock and Diurnal Rhythms of Metabolic Genes in the Liver without Affecting the Suprachiasmatic Nucleus

et al. 2013

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Chronic ethanol consumption disrupts several metabolic pathways including β-oxidation and lipid biosynthesis, facilitating the development of alcoholic fatty liver disease. Many of these same metabolic pathways are directly regulated by cell autonomous circadian clocks, and recent studies suggest that disruption of daily rhythms in metabolism contributes to multiple common cardiometabolic diseases (including non-alcoholic fatty liver disease). However, it is not known whether ethanol disrupts the core molecular clock in the liver, nor whether this, in turn, alters rhythms in lipid metabolism. Herein, we tested the hypothesis that chronic ethanol consumption disrupts the molecular circadian clock in the liver and potentially changes the diurnal expression patterns of lipid metabolism genes. Consistent with previous studies, male C57BL/6J mice fed an ethanol-containing diet exhibited higher levels of liver triglycerides compared to control mice, indicating hepatic steatosis. Further, the diurnal oscillations of core clock genes (Bmal1, Clock, Cry1, Cry2, Per1, and Per2) and clock-controlled genes (Dbp, Hlf, Nocturnin, Npas2, Rev-erbα, and Tef) were altered in livers from ethanol-fed mice. In contrast, ethanol had only minor effects on the expression of core clock genes in the suprachiasmatic nucleus (SCN). These results were confirmed in Per2Luciferase knock-in mice, in which ethanol induced a phase advance in PER2::LUC bioluminescence oscillations in liver, but not SCN. Further, there was greater variability in the phase of PER2::LUC oscillations in livers from ethanol-fed mice. Ethanol consumption also affected the diurnal oscillations of metabolic genes, including Adh1, Cpt1a, Cyp2e1, Pck1, Pdk4, Ppargc1a, Ppargc1b and Srebp1c, in the livers of C57BL/6J mice. In summary, chronic ethanol consumption alters the function of the circadian clock in liver. Importantly, these results suggest that chronic ethanol consumption, at levels sufficient to cause steatosis, disrupts the core hepatic clock as well as the diurnal rhythms of key lipid metabolism genes.

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Section: Discussionmentioning

confidence: 92%

Chronic Ethanol Consumption Disrupts the Core Molecular Clock and Diurnal Rhythms of Metabolic Genes in the Liver without Affecting the Suprachiasmatic Nucleus

et al. 2013

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“…It is therefore conceivable that clock genes play a role in lipid metabolism in the liver and that circadian dysregulation or impairment of the clock mechanism can contribute to the development of NAFLD. For example, in another study by Ando and colleagues, no changes were detected in the rhythmicity of hepatic clock gene expression and rhythmically expressed genes in a mouse model of non-alcoholic steatohepatitis [31]. In this model, mice were fed an atherogenic diet that induced steatosis, inflammation, cellular ballooning, stellate cell activation, hepatic insulin resistance, lipid peroxidation and oxidative stress in the liver.…”

Section: Non-alcoholic Fatty Liver Diseasementioning

confidence: 96%

“…Despite the presence of these extensive pathological changes, the hepatic circadian clock was unimpaired. These findings provide evidence that the circadian clock is protected against alterations in the intracellular environment and that impairment of the circadian clock may present a cause, rather than a consequence, of metabolic disease [31].…”

Section: Non-alcoholic Fatty Liver Diseasementioning

confidence: 97%

Role of biological rhythms in gastrointestinal health and disease

Hoogerwerf

2009

Rev Endocr Metab Disord

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The molecular basis for biological rhythms is formed by clock genes. Clock genes are functional in the liver, within gastrointestinal epithelial cells and neurons of the enteric nervous system. These observations suggest a possible role for clock genes in various circadian functions of the liver and the gastrointestinal tract through the modulation of organ specific clock-controlled genes. Consequently, disruptions in circadian rhythmicity may lead to adverse health consequences. This review will focus on the current understanding of the role of circadian rhythms in the pathogenesis of gastrointestinal- and hepatic disease such as obesity, non-alcoholic fatty liver disease, alcoholic fatty liver disease and alterations in colonic motility.

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“…In contrast to MCD-induced steatohepatitis, animals receiving an atherogenic diet also exhibit systemic insulin resistance, which can be exacer-bated by increasing the fat content [41] . In these models, the expression of genes for fatty acid synthesis, such as SREBP-1c and fatty acid synthase, are upregulated, while the expression levels of genes involved in mitochondrial fatty acid ␤ -oxidation are repressed, resulting in dysregulation of mitochondrial energy production, carbohydrate metabolism and lipid metabolism in hepatocytes [41,42] .…”

Section: Animal Models -Turning Years Into Weeksmentioning

confidence: 99%

Animal Models of Non-Alcoholic Steatohepatitis: Of Mice and Man

Schattenberg

Galle²

2010

Dig Dis

128

109

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The epidemic occurrence of obesity has led to a rapid increase in the incidence of non-alcoholic fatty liver disease (NAFLD) in industrial countries. The disease spectrum includes hepatic steatosis, lobular inflammation with steatohepatitis (NASH) and varying degrees of liver fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma can develop in patients with NASH, even in the absence of cirrhosis. The majority of patients with primary NASH exhibit risk factors that define the metabolic syndrome including insulin resistance and visceral obesity. However, only a minority of patients with NAFLD progress to end-stage liver disease and, so far, predictors to identify these patients are not available. The course of disease progression appears to be slow and develops progressively over years, modulated by genetic susceptibility, nutritional misbehavior and environmental factors. Although risk factors have been identified in epidemiological studies, little is known about disease initiation and progression. This review summarizes the existing animal models of NAFLD, focusing on genetic and dietary models, and discusses their applicability in studying signaling events involved in steatohepatitis. Despite the shortcomings inherent to all experimental models, research in this field has helped to identify potential therapeutic targets and, thus, contributed significantly to our understanding of this disease. The validation and search for new in vivo and in vitro models will propagate the understanding of NASH and help clinicians to develop new treatment modalities.

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The hepatic circadian clock is preserved in a lipid-induced mouse model of non-alcoholic steatohepatitis

Cited by 24 publications

References 40 publications

Chronic Ethanol Consumption Disrupts the Core Molecular Clock and Diurnal Rhythms of Metabolic Genes in the Liver without Affecting the Suprachiasmatic Nucleus

Chronic Ethanol Consumption Disrupts the Core Molecular Clock and Diurnal Rhythms of Metabolic Genes in the Liver without Affecting the Suprachiasmatic Nucleus

Role of biological rhythms in gastrointestinal health and disease

Animal Models of Non-Alcoholic Steatohepatitis: Of Mice and Man

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