gc-1-compound and Atherosclerosis

The article is principally intended to describe the recent evolutions in the field of research concerned with the metabolic actions of thyroid hormones and those of some of their metabolites or derivatives. Mitochondria, as a result of their functions, represent the principal objective of scientists investigating the mechanisms underlying the effects of thyroid hormones or their metabolites/derivatives.. Indeed, some important recent findings concern these organelles, and in particular mitochondrial uncoupling and its modulation by effectors. Traditionally, thyroxine (T4) and tri-iodo-L-thyronine (T3) were the only thyroid hormones considered to have metabolic effects, and they alone were considered for potential as agents that might counteract some important abnormalities such as dyslipidaemias and obesity. Several observations, however, led to a reconsideration of this idea. In recent years, studies dealing with the biological activities of some natural metabolites or structural analogues of thyroid hormones have revealed abilities to ameliorate some major worldwide medical problems, such as artherosclerosis, obesity and cardiovascular diseases. Among natural metabolites, 3,5-diiodothyronine (T2) has been shown to powerfully reduce adiposity and dyslipidaemia and to reverse hepatic steatosis without unfavourable side-effects usually observed when T3 or T4 is used. Examples of synthetic analogues are GC-1 (or sobetirome) and KB2115 (or eprotirome) which show ipolipidaemic and antiaterogenic capacities. Clinical trials are in progress for these last agents.. In view of the above-mentioned actions, some of these compounds are now undergoing clinical trials and may have important implications for clinical practice or researches in the field of both endocrinology and metabolic-related abnormalities such as diabetes and dyslipidaemias.

Topics: Acetates; Adiposity; Anilides; Animals; Atherosclerosis; Cardiovascular Diseases; Clinical Trials as Topic; Diiodothyronines; Dyslipidemias; Energy Metabolism; Fatty Liver; Humans; Lipid Metabolism; Mice; Mitochondria; Obesity; Phenols; Rats; Thyroid Hormones

The aggressive reduction of LDL-cholesterol levels by treatment with statins is a key component of preventive cardiovascular care; however, additional therapies to prevent atherosclerosis and the associated clinical sequelae are still needed. Thyromimetic compounds selective for the liver or for the thyroid hormone receptor isoform beta1 constitute a novel approach for the treatment of dyslipidemia. In preclinical studies, selective thyromimetics significantly reduced plasma cholesterol levels and provided protection from atherosclerosis by upregulating the hepatic LDL receptor and promoting reverse cholesterol transport. Importantly, data from ongoing clinical trials have provided the first evidence that selective thyromimetics may also reduce the levels of plasma cholesterol in humans.

Topics: Acetates; Anilides; Animals; Anticholesteremic Agents; Arteriosclerosis; Atherosclerosis; Biological Transport; Biomimetics; Cholesterol, LDL; Clinical Trials as Topic; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Lipid Metabolism; Malonates; Molecular Structure; Organophosphonates; Phenols; Phenyl Ethers; Phenylacetates; Propionates; Pyridazines; Receptors, LDL; Thyroid Gland; Thyroid Hormones

Inherited abnormalities in apolipoprotein E (ApoE) or low-density lipoprotein receptor (LDLR) function result in early onset cardiovascular disease and death. Currently, the only curative therapy available is liver transplantation. Hepatocyte transplantation is a potential alternative; however, physiological levels of hepatocyte engraftment and repopulation require transplanted cells to have a competitive proliferative advantage of over host hepatocytes. Herein, we aimed to test the efficacy and safety of a novel preparative regimen for hepatocyte transplantation.. Herein, we used an ApoE-deficient mouse model to test the efficacy of a new regimen for hepatocyte transplantation. We used image-guided external-beam hepatic irradiation targeting the median and right lobes of the liver to enhance cell transplant engraftment. This was combined with administration of the hepatic mitogen GC-1, a thyroid hormone receptor-β agonist mimetic, which was used to promote repopulation.. The non-invasive preparative regimen of hepatic irradiation and GC-1 was well-tolerated in ApoE. Significant hepatic repopulation and the cure of dyslipidemia in this model, using a novel and well-tolerated preparative regimen, demonstrate the clinical potential of applying this method to the treatment of inherited metabolic diseases of the liver.. Hepatocyte transplantation is a promising alternative to liver transplantation for the treatment of liver diseases. However, it is inefficient, as restricted growth of transplanted cells in the liver limits its therapeutic benefits. Preparative treatments improve the efficiency of this procedure, but no clinically-feasible options are currently available. In this study we develop a novel well-tolerated preparative treatment to improve growth of cells in the liver and then demonstrate that this treatment completely cures an inherited lipid disorder in a mouse model.

Topics: Acetates; Animals; Apolipoproteins E; Atherosclerosis; Cholesterol; Disease Models, Animal; Dyslipidemias; Female; Hepatocytes; Hyperlipoproteinemia Type II; Male; Mice; Mice, Inbred C57BL; Phenols

Thyroid hormone reduces plasma cholesterol and increases expression of low-density lipoprotein receptor (LDL-R) in liver, an effect mediated by thyroid receptor β (TRβ). The selective TRβ modulator GC-1 also enhances several steps in reverse cholesterol transport and can decrease serum cholesterol independently of LDL-R. To test whether GC-1 reduces atherosclerosis and to determine which mechanisms are active, we treated ApoE deficient mice with atherogenic diet ± GC-1. GC-1 reduced cholesteryl esters in aorta after 20 weeks. Serum free and esterified cholesterol were reduced after 1 and 10 weeks, but not 20 weeks. Hepatic bile acid synthesis and LDL-R expression was elevated after 1, 10 and 20 weeks, without changes in hepatic de novo cholesterol synthesis. GC-1 increased faecal neutral sterols and reduced serum campesterol after 1 week, indicating reduced intestinal cholesterol absorption. After 20 weeks, GC-1 increased faecal bile acids, but not faecal neutral sterols. Hepatic scavenger receptor B1 (SR-B1) expression was decreased by GC-1. We conclude that GC-1 delays the onset of atherosclerosis in ApoE deficient mice. Since ApoE is needed for hepatic cholesterol reabsorption by LDL-R, this supports the idea that GC-1 reduces serum cholesterol independently of LDL-R by increasing hepatic bile acid synthesis. GC-1 lipid-lowering effects in ApoE deficient mice may also be partly due to reduced intestinal cholesterol absorption. Since reductions in serum cholesterol are reversed at longer times, these GC-1 dependent effects may not be enough for sustained cholesterol reduction in long term treatments.

Topics: Acetates; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Bile Acids and Salts; Biological Transport; Cholesterol; Disease Models, Animal; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenols; Phytosterols; Receptors, LDL; Sterols; Thyroid Hormone Receptors beta; Time Factors