CREBH Regulates Systemic Glucose and Lipid Metabolism

Nakagawa, Yoshimi; Shimano, Hitoshi

doi:10.3390/ijms19051396

Cited by 71 publications

(43 citation statements)

References 107 publications

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“…50 It has been proven that there is a cross-talk between glucose and lipid metabolism. 51,52 In this study, we found that FSH upregulated hepatic cholesterol biosynthesis via promoting AKT-dependent FoxO1 phosphorylation. Our team previously found that FSH enhanced gluconeogenesis without effecting insulin, dependent on AMP-activated protein kinase (AMPK) phosphorylation via GRK2 in the liver.…”

Section: Discussionsupporting

confidence: 49%

Blocking FSH inhibits hepatic cholesterol biosynthesis and reduces serum cholesterol

et al. 2018

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Menopause is associated with dyslipidemia and an increased risk of cardio-cerebrovascular disease. The classic view assumes that the underlying mechanism of dyslipidemia is attributed to an insufficiency of estrogen. In addition to a decrease in estrogen, circulating follicle-stimulating hormone (FSH) levels become elevated at menopause. In this study, we find that blocking FSH reduces serum cholesterol via inhibiting hepatic cholesterol biosynthesis. First, epidemiological results show that the serum FSH levels are positively correlated with the serum total cholesterol levels, even after adjustment by considering the effects of serum estrogen. In addition, the prevalence of hypercholesterolemia is significantly higher in peri-menopausal women than that in premenopausal women. Furthermore, we generated a mouse model of FSH elevation by intraperitoneally injecting exogenous FSH into ovariectomized (OVX) mice, in which a normal level of estrogen (E2) was maintained by exogenous supplementation. Consistently, the results indicate that FSH, independent of estrogen, increases the serum cholesterol level in this mouse model. Moreover, blocking FSH signaling by anti-FSHβ antibody or ablating the FSH receptor (FSHR) gene could effectively prevent hypercholesterolemia induced by FSH injection or high-cholesterol diet feeding. Mechanistically, FSH, via binding to hepatic FSHRs, activates the Gi2α/β-arrestin-2/Akt pathway and subsequently inhibits the binding of FoxO1 with the SREBP-2 promoter, thus preventing FoxO1 from repressing SREBP-2 gene transcription. This effect, in turn, results in the upregulation of SREBP-2, which drives HMGCR nascent transcription and de novo cholesterol biosynthesis, leading to the increase of cholesterol accumulation. This study uncovers that blocking FSH signaling might be a new strategy for treating hypercholesterolemia during menopause, particularly for women in peri-menopause characterized by FSH elevation only.

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Section: Discussionsupporting

confidence: 49%

Blocking FSH inhibits hepatic cholesterol biosynthesis and reduces serum cholesterol

et al. 2018

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“…Studies have shown that the plasma FGF-21 concentration level in the GLP-1Ra intervention group is significantly higher than that in the placebo control group, suggesting that it can participate in regulating liver lipid metabolism by regulating FGF-12 levels. At the same time, studies have shown that cAMP-responsive elementbinding protein H (CREBH) and peroxisome proliferator activated receptor α (PPARα) in the liver mutual coordination plays an important role in regulating lipid metabolism [37,38]. The CREBH-PPARα-FGF21 axis is an indispensable part of the liver involved in mediating lipid and sugar metabolism.…”

Section: Discussionmentioning

confidence: 99%

The effect of liraglutide on nonalcoholic fatty liver disease in type 2 diabetes mellitus

Zhang

Bai

Jia

et al. 2020

Int J Diabetes Dev Ctries

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Aims The objective is to investigate the effects of liraglutide on nonalcoholic fatty liver disease in type 2 diabetes mellitus. Materials and methods Thirty-two patients with T2DM and NAFLD admitted to the Third Affiliated Hospital of Dalian Medical University from December 2014 to December 2016 were selected, including 11 females and 21 males, aged 39.34 ± 8.54 years old. The patients were given liraglutide on the basis of their original hypoglycemic regimen.

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“…CREBH is primarily expressed in the endoplasmic reticulum (ER) of cells in the liver and small intestine [ 79 , 80 ]. CREBH expression increases in response to fasting through glucagon signaling [ 81 ].…”

Section: Lipid Metabolismmentioning

confidence: 99%

Transcriptional Regulation in Non-Alcoholic Fatty Liver Disease

2020

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Obesity is the primary risk factor for the pathogenesis of non-alcoholic fatty liver disease (NAFLD), the worldwide prevalence of which continues to increase dramatically. The liver plays a pivotal role in the maintenance of whole-body lipid and glucose homeostasis. This is mainly mediated by the transcriptional activation of hepatic pathways that promote glucose and lipid production or utilization in response to the nutritional state of the body. However, in the setting of chronic excessive nutrition, the dysregulation of hepatic transcriptional machinery promotes lipid accumulation, inflammation, metabolic stress, and fibrosis, which culminate in NAFLD. In this review, we provide our current understanding of the transcription factors that have been linked to the pathogenesis and progression of NAFLD. Using publicly available transcriptomic data, we outline the altered activity of transcription factors among humans with NAFLD. By expanding this analysis to common experimental mouse models of NAFLD, we outline the relevance of mouse models to the human pathophysiology at the transcriptional level.

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CREBH Regulates Systemic Glucose and Lipid Metabolism

Cited by 71 publications

References 107 publications

Blocking FSH inhibits hepatic cholesterol biosynthesis and reduces serum cholesterol

Blocking FSH inhibits hepatic cholesterol biosynthesis and reduces serum cholesterol

The effect of liraglutide on nonalcoholic fatty liver disease in type 2 diabetes mellitus

Transcriptional Regulation in Non-Alcoholic Fatty Liver Disease

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