Gender Disparity of Hepatic Lipid Homoeostasis Regulated by the Circadian Clock

Yang, Xiaoxia; Zhang, Yu Kun Jennifer; Esterly, Noriko; Klaassen, Curtis D.; Wan, Yu‐Jui Yvonne

doi:10.1093/jb/mvp018

Cited by 31 publications

(31 citation statements)

References 42 publications

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“…Our data in humans are consistent with a previous report in mouse livers showing that the expression of clock genes differed between male and female, being higher in females [21]. …”

Section: Discussionsupporting

confidence: 93%

Sexual Dimorphism in Clock Genes Expression in Human Adipose Tissue

et al. 2011

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Background This study was carried out to investigate whether sex-related differences exist in the adipocyte expression of clock genes from subcutaneous abdominal and visceral fat depots in severely obese patients. Methods We investigated 16 morbidly obese patients, eight men and eight women (mean age 45±20 years; mean BMI 46±6 kg/m2), undergoing laparoscopic gastric bypass surgery. Biopsies were taken as paired samples [subcutaneous and visceral adipose tissue (AT)] at the beginning of the surgical process at 11:00 h in the morning. Metabolic syndrome features such as waist circumference, plasma glucose, triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were also studied. The expression of clock genes (PER2, BMAL1, and CRY1) was measured by quantitative real-time PCR, Western blot, and immunohistochemical analysis. Results Gene expression was significantly higher in women than in men for the three genes studied in both ATs (P<0.05). In visceral fat, these differences were more marked. (P<0.001). Western blot analysis partially confirmed these results since statistical differences were observed for PER2 in both ATs and for CRY1 in subcutaneous adipose tissue. There were no differences in BMAL1 protein expression. Interestingly, clock gene expression level was correlated with LDL-C and HDL-C (P<0.05). Moreover, we found significant associations with body fat mass in women and with age in men. Conclusions Clock genes expression is sex dependent in human adipose tissue from morbidly obese subjects and correlates to a decreased in metabolic syndrome-related traits. These preliminary results make necessary to go deep into the knowledge of the molecular basis of the sexual dimorphism in chronobiology.

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“…Our data in humans are consistent with a previous report in mouse livers showing that the expression of clock genes differed between male and female, being higher in females [21]. …”

Section: Discussionsupporting

confidence: 93%

Sexual Dimorphism in Clock Genes Expression in Human Adipose Tissue

et al. 2011

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“…Our work 50 and those of others 25 have established that PPARs (α, β, and γ) are circadian genes. Among our studies is expression profiling of the diurnal hepatic genes encoding circadian clocks, nuclear receptors, and lipid metabolic enzymes.…”

Section: Nuclear Receptors and Hepatocyte Proliferationsupporting

confidence: 62%

“…Among our studies is expression profiling of the diurnal hepatic genes encoding circadian clocks, nuclear receptors, and lipid metabolic enzymes. 50 The Cosinor analysis revealed that several genes encoding nuclear receptors, including PPARs and lipid metabolizing enzymes, and genes whose expressions are regulated by PPARs, are rhythmically expressed in phase with peripheral clocks. These correlate with diurnal changes of hepatic lipid levels.…”

Section: Nuclear Receptors and Hepatocyte Proliferationmentioning

confidence: 99%

Retinoic Acid-mediated Nuclear Receptor Activation and Hepatocyte Proliferation

Bushue

Wan

2009

Journal of Experimental & Clinical Medicine

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Due to their well-known differentiation and apoptosis-inducing abilities, retinoic acid (RA) and its analogs have strong anti-cancer efficacy in human cancers. However, in vivo RA is a liver mitogen. While speculation has persisted that RA-mediated signaling is likely involved in hepatocyte proliferation during liver regeneration, direct evidence is still required. Findings in support of this proposition include observations that a release of retinyl palmitate (the precursor of RA) occurs in liver stellate cells following liver injury. Nevertheless, the biological action of this released vitamin A is virtually unknown. More likely is that the released vitamin A is converted to RA, the biological form, and then bound to a specific receptor (retinoid x receptor; RXRα), which is most abundantly expressed in the liver. Considering the mitogenic effects of RA, the RA-activated RXRα would likely then influence hepatocyte proliferation and liver tissue repair. At present, the mechanism by which RA stimulates hepatocyte proliferation is largely unknown. This review summarizes the activation of nuclear receptors (peroxisome proliferator activated receptor-α, pregnane x receptor, constitutive androstane receptor, and farnesoid x receptor) in an RXRα dependent manner to induce hepatocyte proliferation, providing a link between RA and its proliferative role.

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“…Notably PPARα, regulated by hormones and cAMP, holds a key role in integrating the mammalian clock and energy metabolism (119) and notably influences Tspo transcriptional regulation (48). Since gender based differences have been observed previously in metabolic patterns of circadian rhythms (120) , this may be an explanation for the gender-based differences in body weight seen in Tspo -/-mice. This is particularly interesting as it could reveal a therapeutic potential for TSPO ligands in the development of gender-based personalized medicine for human diseases relating to metabolic disorders, which are often linked to circadian disruption (121).…”

Section: Tspo -/-Knockout Mice: New Insights Of An Old Functionmentioning

confidence: 52%

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Gatliff

Campanella

2016

Biochemical Journal

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The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

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Gender Disparity of Hepatic Lipid Homoeostasis Regulated by the Circadian Clock

Cited by 31 publications

References 42 publications

Sexual Dimorphism in Clock Genes Expression in Human Adipose Tissue

Sexual Dimorphism in Clock Genes Expression in Human Adipose Tissue

Retinoic Acid-mediated Nuclear Receptor Activation and Hepatocyte Proliferation

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

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