Novel insights into the pathological development of dyslipidemia in patients with hypothyroidism

Abstract

According to the previous reports, hypothyroidism has been shown to be strongly correlated with increased circulating concentrations of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). Notably, thyroid hormones are confirmed to modulate the production, clearance, and transformation process of cholesterol within circulation of mammals. Moreover, emerging evidence suggests that the thyroid-stimulating hormone could also participate in modulating serum lipid metabolism independently of thyroid hormones, which further induces the pathological development of dyslipidemia. However, the underlying mechanism is still not fully elucidated. Recently, several research studies have demonstrated that the pathogenic progression of hypothyroidism-related dyslipidemia might be correlated with the decreased serum concentrations of thyroid hormones and the increased serum concentrations of thyroid-stimulating hormones. Thus, this indicates that hypothyroidism could induce dyslipidemia and its related cardio-metabolic disorder diseases. In addition, several newly identified modulatory biomarkers, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein (ANGPTLs), and fibroblast growth factors (FGFs), might play an important role in the regulation of dyslipidemia induced by hypothyroidism. Furthermore, under the status of hypothyroidism, significantly dysfunctional HDL particles could also be observed. In the current review, we summarized the recent knowledge of the relationship between the development of hypothyroidism with dyslipidemia. We also discussed the updated understanding of the mechanisms whereby hypothyroidism induces the risk and the development of dyslipidemia and cardio-metabolic diseases.

FIGURE 1

Effects of thyroid hormones and thyroid-stimulating hormones on lipid metabolism in hypothyroidism. Thyroid hormones decrease in hypothyroidism, then DNL and the activity of HMGCR reduces, leading to declined cholesterol production, but FFA β-oxidation also decreases. TH reduction reduces the activity of CYP7A1 and ABCG5/8 to reduce cholesterol clearance. In general, TG-rich VLDL level is increased in hypothyroidism, and the elevation of NPC1L1 concentration leads to an increase of TG-rich CM. DNL: de novo lipogenesis; FFA: Free fatty acid, TG: triglyceride; RLP: Remnant lipoprotein; NPC1L1: Niemann-Pick C1-like 1 protein; VLDL: Very low-density lipoprotein; ANGPTL3/8: Angiogenin-like protein3/8; ApoC3: Apolipoprotein C3; CETP: Cholesterol transport protein transporter; HL: Hepatic lipidosis; PLTP: Phospholipid transfer protein; LCAT: Lecithin cholesterol acyltransferase; ABCA1: ATP-binding cassette transporter A1; SRB1: Scavenger receptor b1; FGF19/21: Fibroblast growth factors 19/21; HMG-CoA: 3-Hydroxy-3-methyl glutaryl coenzyme A; ACC: Acetyl-CoA carboxylase; FAS: Fatty acid synthase; CM: Chylomicron; ABCG5/8: ATP-binding cassette transporter G5/8; CYP7A1: Cholesterol 7α-hydroxylase; HMGCR: HMG-COA reductase