Thyroid stimulating hormone exhibits the impact on LDLR/LDL-c via up-regulating hepatic PCSK9 expression

Gong, Yingyun; Ma, Yi-Ping; Ye, Zhengqin; Fu, Zhen-Yan; Yang, Panpan; Gao, Beibei; Guo, Wen; Hu, Dandan; Ye, Jingya; Ma, Shuai; Zhang, Fan; Zhou, Li; Xu, Xinyu; Li, Zhong; Yang, Tao; Zhou, Hongwen

doi:10.1016/j.metabol.2017.07.006

Cited by 43 publications

(27 citation statements)

References 37 publications

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“…Gong et al demonstrated that patients with subclinical hypothyroidism have increased serum PCSK9 levels, whose expression is enhanced in rhTSH-treated HepG2 cells through the activation of SREBP1c and SREBP2. Consequently, LDL uptake is decreased resulting in increased plasma concentration of LDL [17]. Additional studies suggest that TSH limits hepatic bile acids synthesis through SREBP2 signalling pathway, thus reinforcing the hypothesis that TSH may regulate lipids metabolism independently by thyroid hormone [25].…”

Section: Discussionmentioning

confidence: 68%

“…The hypothesis that TSH can directly increase the lipids level is relatively recent, and based on associated studies not only in patients with increased TSH level (e.g., subclinical/overt hypothyroidism), but also in subjects with TSH within the normal reference range [16]. Indeed, TSH can contribute to increase LDLc by increasing the Proprotein convertase subtilisin/kexin type 9 (PCSK9) [17].…”

Section: Introductionmentioning

confidence: 99%

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Effect of rhTSH on Lipids

Delitala

Scuteri

Maioli

et al. 2020

JCM

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Background: Subclinical hypothyroidism is associated with increased blood lipid levels. However, the exact role of thyrotropin (TSH) alone is not clear. In order to clarify this point, we analysed the acute effect of recombinant human TSH (rhTSH) administration on lipid levels. Methods: Sera of 27 premenopausal women with well-differentiated thyroid cancer were analysed. Patients that underwent a total thyroidectomy, ablation with 131I (Iodine 131) and rhTSH administration as a part of routine follow-up American Thyroid Association guidelines were included. The protocol consists of 2 intramuscular injections of 0.9 mg of rhTSH, performed on day 1 day and day 2, with blood collection on day 1 (before rhTSH administration), and day 5. TSH, free thyroxine, total cholesterol, low-density lipoprotein cholesterol (LDLc), high density lipoprotein cholesterol (HDLc), and triglycerides were assessed in all the samples, before and four days after the first administration of rhTSH. Results: Total cholesterol and triglycerides significantly increased after stimulation of rhTSH (respectively, 192 ± 33 vs. 207 ± 26, p = 0.036 and 72 ± 23 vs. 85 ± 23, p = 0.016). LDLc and HDLc showed comparable concentrations before and after the test (respectively, 115 ± 27 vs. 126 ± 22, p = 0.066, and 62 ± 15 vs. 64 ± 15, p = 0.339), while non-HDLc increased after stimulation (130 ± 30 vs. 143 ± 25, p = 0.045). Conclusion: TSH has a direct effect on total cholesterol, triglycerides, and nonHDLc. Explanation of these phenomena will require additional studies.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Effect of rhTSH on Lipids

Delitala

Scuteri

Maioli

et al. 2020

JCM

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“…Recently, a direct relationship between serum TSH and PCSK9 expression and an inverse relationship between serum TSH and LDLR expression were demonstrated (99). PCSK9 inhibitors are effective in lowering serum cholesterol levels via recruitment of LDL-C from circulation by restoring LDLR expression on the cell surface of hepatocytes.…”

Section: Tsh and Lipid Metabolismmentioning

confidence: 99%

“…PCSK9 inhibitors are effective in lowering serum cholesterol levels via recruitment of LDL-C from circulation by restoring LDLR expression on the cell surface of hepatocytes. Recombinant human TSH alpha/beta heterodimer protein increases PCSK9 mRNA expression and protein levels and impairs LDL-C uptake in human liver cells (99,100). TSHR −/− mice supplemented with T4 also have lower intrahepatic TAG levels both after chow and HFD and lower expression of lipogenic genes than control mice under the same conditions, suggesting that TSH may also regulate intrahepatic lipid metabolism (100).…”

Section: Tsh and Lipid Metabolismmentioning

confidence: 99%

Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists

Sinha

Bruinstroop

Singh

et al. 2019

Thyroid

175

131

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Background-Thyroid hormones (THs) exert a strong influence on mammalian lipid metabolism at the systemic and hepatic levels by virtue of their roles in regulating circulating lipoprotein, triglyceride (TAG), and cholesterol levels, as well as hepatic TAG storage and metabolism. These effects are mediated by intricate sensing and feedback systems that function at the physiological, metabolic, molecular, and transcriptional levels in the liver. Dysfunction in the pathways involved in lipid metabolism disrupts hepatic lipid homeostasis and contributes to the pathogenesis of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and hypercholesterolemia. There has been strong interest in understanding and employing THs, TH metabolites, and TH mimetics as lipid-modifying drugs. Summary-THs regulate many processes involved in hepatic TAG and cholesterol metabolism to decrease serum cholesterol and intrahepatic lipid content. TH receptor β analogs designed to have less side effects than the natural hormone are currently being tested in phase II clinical studies for NAFLD and hypercholesterolemia. The TH metabolites, 3,5-diiodo-L-thyronine (T2) and T1AM (3-iodothyronamine), have different beneficial effects on lipid metabolism compared with triiodothyronine (T3), although their clinical application is still under investigation. Also, prodrugs and glucagon/T3 conjugates have been developed that direct TH to the liver. Conclusions-TH-based therapies show clinical promise for the treatment of NAFLD and hypercholesterolemia. Strategies for limiting side effects of TH are being developed and may enable TH metabolites and analogs to have specific effects in the liver for treatments of these conditions. These liver-specific effects and potential suppression of the hypothalamic/pituitary/

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“…Besides these transcription factors, recent work has shown that thyroid-stimulating hormone (TSH) increases PCSK9 mRNA expression in HepG2 cell line ( Figure 1A). Moreover, circulating TSH levels in subclinical hypothyroid patients correlate with plasma LDL-C and PCSK9, suggesting a role for TSH in cholesterol metabolism [32]. Finally, the major metabolite of berberine, berberrubine, has been proposed to exert potent inhibitory effect on PCSK9 through a pathway involving extracellular signal regulated kinase (ERK), which results in higher LDLR levels in cellular models, awaiting in vivo testing [33].…”

Section: Pcsk9 Regulationmentioning

confidence: 99%

Proprotein convertase subtilisin/kexin type 9 and lipid metabolism

Spolitu

Dai

Zadroga

et al. 2019

Current Opinion in Lipidology

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Purpose of review: The purpose of this review is to highlight the recent findings of one of the most promising therapeutic targets in low-density lipoprotein (LDL) cholesterol management, proprotein convertase subtilisin/kexin type 9 (PCSK9). Recent findings: Endoplasmic reticulum (ER) cargo receptor, surfeit locus protein 4 (SURF4) interacts with PCSK9 and regulates its exit from ER and its secretion. Once secreted, PCSK9 binds to heparin sulfate proteoglycans on the hepatocyte surface and this binding is required for PCSK9-LDL receptor (LDLR) complex formation and LDLR degradation. Post-transcriptionally, recent work has shown that PCSK9 gets degraded in the lysosomes by activation of the glucagon receptor signaling, providing more data on the hormonal regulation of PCSK9. Finally, human studies with PCSK9 inhibitors offered more evidence on their benefits and safe use. Summary: Recent work on the regulation of PCSK9 has enhanced our understanding of its biology, which may provide important information for future PCSK9-based therapies.

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Thyroid stimulating hormone exhibits the impact on LDLR/LDL-c via up-regulating hepatic PCSK9 expression

Cited by 43 publications

References 37 publications

Effect of rhTSH on Lipids

Effect of rhTSH on Lipids

Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists

Proprotein convertase subtilisin/kexin type 9 and lipid metabolism

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