Background: Subclinical hypothyroidism is associated with dyslipidemia and atherosclerosis. Whether these effects are in part mediated via direct effects of thyrotropin (TSH) on peripheral thyroid hormone (TH) metabolism and/or concentrations of serum lipids is not clear. Objective: This study examined whether TSH has direct effects on peripheral TH metabolism and serum lipids. Methods: Eighty-two patients with differentiated thyroid cancer were retrospectively analyzed. All patients had undergone total thyroidectomy and 131I remnant ablation. During follow-up, two successive injections of recombinant human TSH (rhTSH) were administered to patients on a stable dose of levothyroxine. In all patients, TSH, thyroxine (T4), free T4 (fT4), triiodothyronine (T3), reverse T3 (rT3), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, lipoprotein(a), and triglyceride levels were measured immediately before the first and approximately 72 hours after the second injection of rhTSH. Results: After rhTSH stimulation, T3 values decreased (from 1.91 to 1.81 nmol/L; p < 0.001). T4, fT4, and rT3 did not change. After rhTSH, median apolipoprotein B increased from 0.90 to 0.92 g/L (p = 0.03), lipoprotein(a) from 0.21 to 0.24 g/L (p < 0.001), and triglycerides from 1.98 to 2.50 mmol/L (p < 0.001). Serum high-density lipoprotein cholesterol decreased from 0.98 to 0.81 mmol/L (p < 0.001). Multiple regression analysis showed that the changes in lipids were most closely associated with the decrease in T3 levels. Conclusions: TSH has direct effects on peripheral TH metabolism by decreasing T3 levels in levothyroxine-treated thyroidectomized patients. This decrease in T3 levels is accompanied by unfavorable changes in serum lipids.
Abstract Aim Bile acids (BAs) are implicated in the pathogenesis of several metabolic syndrome‐related diseases, including insulin resistance (IR) and type 2 diabetes (T2D). It has been reported that IR and T2D are associated with an increased ratio of 12α/non‐12α‐hydroxylated BAs in the circulating BA pool. It is, however, unknown whether the improvement of insulin sensitivity inversely affects BA composition in humans. Therefore, we assessed whether lifestyle‐induced weight loss induces changes in BA metabolism in people with obesity, with or without T2D, and if these changes are associated with metabolic parameters. Materials and Methods Individual BAs and C4 were quantified by ultra‐high‐performance liquid chromatography‐tandem mass spectrometry in plasma samples collected from two cohorts of people with obesity (OB) and with T2D and obesity (T2D), before and after a lifestyle intervention. Results Lifestyle‐induced weight loss improved glycaemic control in both cohorts, with plasma BA concentrations not affected by the lifestyle interventions. The ratio of 12α/non‐12α‐hydroxylated BAs remained unchanged in OB ( p = .178) and even slightly increased upon intervention in T2D ( p = .0147). Plasma C4 levels were unaffected in OB participants ( p = .20) but significantly reduced in T2D after intervention ( p = .0003). There were no significant correlations between the ratio of 12α/non‐12α‐hydroxylated BAs and glucose, insulin, or homeostatic model assessment‐IR, nor in plasma triglycerides, low‐density lipoprotein cholesterol, lipoprotein (a) in the T2D cohort. Conclusions Lifestyle‐induced weight loss did improve glycaemic control but did not affect BA concentrations. Improvements in insulin sensitivity were not associated with changes in BA parameters in people with obesity, with or without T2D.
Rationale: People with heterozygous familial hypercholesterolemia (FH) have a genetic predisposition for developing premature cardiovascular disease (CVD). However the clinical phenotype of FH has a high variability which is due to metabolic and environmental factors. One of the metabolic factors that increase the risk for pre-mature CVD might be Lp(a). Previous studies have identified Lp(a) as an independent risk factor for cardiovascular disease. The goal of our study was to analyze the association between calcium scores and coronary plaque burden in relation with plasma Lp(a) levels in patients with FH and to study whether this association was similar in men and women. Methods and results: From February 2008 until June 2011 145 (93 men, age 52±8) patients with a clinical diagnosis of FH visiting the outpatient clinic for lipid disorders in the Medical Centre were included. These patients underwent a CT coronary angiography to determine the coronary plaque burden and calcium score. From 131 (84 men, age 53±8) of these patients blood was collected and Lp(a) levels were measured. Lp(a) levels were subsequently related to total coronary calcium score(TCS) and coronary plaque burden. Coronary plaque burden is described as diseased coronary segment score per patient (DSS). DDS and TCS were analyzed in a group with low Lp(a) <0,300 g/L and with high Lp(a) >1,000 g/L levels, adjusted for sex, using the Mann-Whitney U test. In men no significant differences in DSS (p=0,960) and TCS (p=0,400) were found if Lp(a) was determined. In women significantly higher DSS (p=0,022) and TCS (p=0,004) were found in the high-Lp(a) group. Conclusion: Our data show a higher amount of DSS and TCS in women with high Lp(a) levels in comparison with women with a low Lp(a). In men no difference in DSS and TCS is found between high and low Lp(a) groups. We show that serum levels of Lp(a) is associated with disease severity in FH women and not in FH men. Clinical relevance: High LP(a) levels in FH women are associated with advanced subclinical atherosclerosis. Therefore, we can identify a high risk subgroup in which we should attain an even more strict cardiovascular risk reduction.
LR11, also called SORLA, is a 250-kDa single transmembrane receptor, belonging to both LDL-receptor and Vps10p receptor family. LR11 is abundantly and specifically expressed in intima smooth muscle cells and regulates its migration. Plasma soluble form of LR11 (sLR11) is positively correlated with the intima-media thickness and has been promoted as a risk factor for coronary artery disease (CAD). Here we studied the role of LR11 in lipid-related gene expression and CAD development, using both Familial Hypercholesterolemia (FH) patients and animal models. LDLR-KO and ApoE-KO mice were fed with either chow or Western type diet (WTD) and their livers were examined. LR11 mRNA and protein expression were elevated in LDLR-KO mice on chow diet but not in ApoE-KO, compared to wild-type controls. WTD further increased LR11 level in both KO strains. SORT1, another Vps10p family member, expression was decreased only in LDLR-KO fed with WTD. To further elucidate the effect of diet, human hepatocytes and hepatic stellate cells were exposed to chylomicrons, LDL and crude fish oil. Chylomicrons increased LR11 mRNA expression in hepatocytes but not stellate cells. For human study, fasting plasma of adult FH patients with and without CAD when ‘off’ statin and of their healthy non-FH brothers were collected. Plasma sLR11 level of FH with CAD is higher when compared to their healthy brothers while no difference was shown in FH without CAD compared to their healthy brothers. A similar trend was observed in plasma sLR11 of LDLR-KO mice on chow diet. We concluded that LR11 is upregulated in an absence of LDL receptor which is markedly affected by diet and triglyceride-rich lipoprotein showed a similar effect in an in vitro setting. Plasma sLR11 correlated with the development of atherosclerosis/CAD. sLR11 may be used as an additional risk factor for CAD in FH patients.
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