Targeting thyroid hormone receptor-β agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index

Erion, Mark D.; Cable, Edward Earl; Ito, Bruce R.; Jiang, Hangyi; Fujitaki, James M.; Finn, Patricia D.; Zhang, Baohong; Hou, Jinzhao; Boyer, Serge H.; Poelje, Paul D. van; Linemeyer, David L.

doi:10.1073/pnas.0702759104

Cited by 195 publications

(211 citation statements)

References 48 publications

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“…Thyroid hormones induce their effects on lipid metabolism via thyroid hormone receptor β, which is expressed in liver (45). Thyroid hormone receptor activation results in a reduction in body weight and fat as well as a decrease in cholesterol and triglyceride levels, which takes place only in hepatocytes (46,47). Our study would confirm the correlation between NAFLD and thyroid dysfunction and a correlation between the TSH level and triglycerides (P =0.003).…”

Section: Discussionsupporting

confidence: 78%

Association and impact of non-alcoholic fatty liver disease on thyroid function

2017

Int. J. Curr. Res. Med. Sci.

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Nonalcoholic fatty liver disease (NAFLD) means accumulation of fat mainly triglyceride exceeding 5 % of liver weight, affecting approximately 20% of population in developed countries. Thyroid dysfunction have been frequently associated with non-alcoholic fatty liver disease. The aim of this study is to determine any association between nonalcoholic fatty liver disease and thyroid dysfunction and to evaluate the impact of non-alcoholic fatty liver disease on thyroid function tests. Subjects and methods: This study was carried out on sixty adult men and women with nonalcoholic fatty liver disease and sixty age-and sex-matched males and females without the disease. NAFLD patients were subjected to a full assessment of medical history, physical examination, abdominal ultrasonography as well as routine laboratory tests. Patients and controls underwent liver function and thyroid function testing including thyroid antibodies. Results: Thirteen patients with NAFLD (21.7%) were found to have thyroid dysfunction. The most common thyroid dysfunction was subclinical hypothyroidism which was found in 10 (16.7%) NAFLD patients followed by overt hypothyroidism in 3 patients (5%). There were statistically significant difference between patients and controls as regard to TSH (p=0.0001), FT4 (p=0.005), FT3 (P=0.043), anti-TPO (p=0.047), anti-TG (p=0.001), IR (p=0.024), insulin (p=0.002), and Leptin (p=0.002). TSH concentration was significantly correlated with ALT (r= 0.381), GGT (r=0.354), HbA1C (r=0.288), triglyceride (r=0.368), FT4 (r=0.414), FT3(r=0.231), anti-TPO(r=0.298), serum insulin (r= 0.287), insulin resistance (IR) (r= 0.453), and serum Leptin (r=0.360) levels.In our patients, hepatic steatosis in the form of increased liver echogenecity was present in almost all patients (100%), and hepatomegaly in twenty-four patients (40%). Thus. Hepatic steatosis were correlated significantly with ALT, GGT, HbA1C, triglyceride, HDL-C, TSH, FT4, FT3, anti-TPO, anti-TG, serum insulin, insulin resistance (IR), and serum Leptin. Conclusion: Thyroid dysfunctions are common in NAFLD patients, with subclinical hypothyroidism hypothyroidism being the most prevalent one. Hepatic steatosis has shown an evident positive correlation with elevated TSH as well as thyroid autoantibodies.

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Section: Discussionsupporting

confidence: 78%

Association and impact of non-alcoholic fatty liver disease on thyroid function

2017

Int. J. Curr. Res. Med. Sci.

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“…This molecule exhibits increased TR activation in the liver relative to extrahepatic tissues and an improved therapeutic index (319). MB07811 undergoes first-pass hepatic extraction and cleavage, generating the TR agonist MB07344 that distributes poorly into most tissues and is rapidly eliminated in the bile (319). MB07811 lowers serum cholesterol in hypercholesterolemic rats, rabbits, monkeys, and humans beyond what was achieved with statins alone (325), is superior to a TRb-selective agonist in the diet-induced obese mouse model (319), and reduces hepatic steatosis in rats and mice models (326).…”

Section: Bianco Et Almentioning

confidence: 99%

Section: Bianco Et Almentioning

confidence: 99%

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

Bianco

Anderson

Forrest

et al. 2014

Thyroid

164

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“…In the liver, the ␤ isoform of the thyroid hormone receptor (TR␤) is responsible for mediating the majority of the actions of tri-iodothyronine (T3), 2 whereas in other tissues such as the heart and brown adipose tissue, the ␣ isoform (TR␣) is the main mediator of thyroid hormone effects (3,4). FGF21 is a member of the endocrine FGF subfamily, which also includes FGF19 and FGF23, all of which circulate and have hormone-like actions (5,6).…”

mentioning

confidence: 99%

Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

Adams

Astapova

Fisher

et al. 2010

Journal of Biological Chemistry

117

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Thyroid hormone has profound and diverse effects on liver metabolism. Here we show that tri-iodothyronine (T3) treatment in mice acutely and specifically induces hepatic expression of the metabolic regulator fibroblast growth factor 21 (FGF21). Mice treated with T3 showed a dose-dependent increase in hepatic FGF21 expression with significant induction at doses as low as 100 g/kg. Time course studies determined that induction is seen as early as 4 h after treatment with a further increase in expression at 6 h after injection. As FGF21 expression is downstream of the nuclear receptor peroxisome proliferatoractivated receptor ␣ (PPAR␣), we treated PPAR␣ knock-out mice with T3 and found no increase in expression, indicating that hepatic regulation of FGF21 by T3 in liver is via a PPAR␣-dependent mechanism. In contrast, in white adipose tissue, FGF21 expression was suppressed by T3 treatment, with other T3 targets unaffected. In cell culture studies with an FGF21 reporter construct, we determined that three transcription factors are required for induction of FGF21 expression: thyroid hormone receptor ␤ (TR␤), retinoid X receptor (RXR), and PPAR␣. These findings indicate a novel regulatory pathway whereby T3 positively regulates hepatic FGF21 expression, presenting a novel therapeutic target for diseases such as non-alcoholic fatty liver disease.The biochemical pathways mediating the metabolism of carbohydrates, lipids, and proteins are all regulated to some degree by thyroid hormone and the thyroid hormone receptors (␣ and ␤) (1, 2), which belong to the nuclear hormone receptor superfamily (1). In the liver, the ␤ isoform of the thyroid hormone receptor (TR␤) is responsible for mediating the majority of the actions of tri-iodothyronine (T3), 2 whereas in other tissues such as the heart and brown adipose tissue, the ␣ isoform (TR␣) is the main mediator of thyroid hormone effects (3, 4). FGF21 is a member of the endocrine FGF subfamily, which also includes FGF19 and FGF23, all of which circulate and have hormone-like actions (5, 6). FGF21 is known to stimulate glucose uptake in mouse 3T3-L1 adipocytes and in primary cultures of human adipocytes and can improve glucose homeostasis when administered to obese mice (6) and non-human primates (7). Transgenic mice overexpressing FGF21 in liver display improved insulin sensitivity and glucose clearance, reduced plasma triglyceride concentrations, and are resistant to weight gain when fed a high fat diet (6).Subsequent studies showed that administration of FGF21 to mice with high fat diet-induced obesity led to increased fat utilization and energy expenditure and reduced plasma glucose, insulin, serum lipid concentrations, and hepatic triglyceride concentrations (6,8). In one study, it was shown that the decrease in hepatic triglyceride concentrations was accompanied by a decrease in lipogenic gene expression (8).FGF21 expression is known to be downstream of the nuclear receptor PPAR␣, which itself plays a significant role in lipid oxidation. FGF21 is physiologically induced u...

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Targeting thyroid hormone receptor-β agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index

Cited by 195 publications

References 48 publications

Association and impact of non-alcoholic fatty liver disease on thyroid function

Association and impact of non-alcoholic fatty liver disease on thyroid function

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

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