GCG-T3 Dyslipidemia · Validation and Molecular Characterization of Novel Glucagon-Thyroid Hormone Conjugates for the Efficient Management of Dyslipidemia and Fatty Liver Disease

Validation and Molecular Characterization of Novel Glucagon-Thyroid Hormone Conjugates for the Efficient Management of Dyslipidemia and Fatty Liver Disease

Cardiovascular disease (CDV) is one of the main causes of death worldwide. Elevated levels of blood lipids (dyslipidemia) is a well-documented risk factor for CVD. Particularly, elevated low-density lipoprotein cholesterol (LDL-C) levels are known to play a critical role in the development of this pathology. For this reason, lowering LDL-C levels is one of the main strategies to either prevent or treat CVD. Among the currently available lipid-lowering agents, the role of statins in reducing CVD has been clearly established. This intervention provides relevant reductions in circulating cholesterol and lowers coronary heart disease risk. However, a considerable number of patients treated with statins fail to meet target reductions in cholesterol and a series of side effects have been described after treatment with this drug. Fatty liver disease (FLD), the most frequent liver metabolic disease caused by excess lipid accumulation in the liver, is also considered a risk factor for CVD since it alters serum lipids and lipoprotein profile. Importantly, there are no approved pharmacological therapies for FLD, only lifestyle changes are recommended as a therapeutic intervention. All these factors emphasize the need to develop novel, efficacious and safe therapeutic tools for the treatment of dyslipidemia and FLD that may offer an advancement for treatment of the metabolic syndrome and contribute to decrease mortality risk from cardiovascular events. In this context, the host group pioneered the development of a new poly-pharmaceutical procedure that allows for peptide-mediated selective tissue targeting of a nuclear hormone, which was proved to be effective for the treatment of obesity. This peptide-based targeting strategy improved the metabolic profile through synergistic co-agonism between both molecules (peptide-nuclear hormone), but also circumvented the potential adverse effects in tissues not expressing the peptide hormone receptor. Based on this innovative concept, we proposed in the current project to develop a novel poly-pharmaceutical therapy for the treatment of dyslipidemia, FLD and the metabolic syndrome by combining two key molecules in the control of metabolic homeostasis: glucagon (a peptide that targets mainly the liver) and thyroid hormone (nuclear hormone implicated in energy metabolism). Glucagon plays an important role in glucose homeostasis, lipid metabolism and energy balance. The weight-lowering and hypolipidemic effects of glucagon make it an attractive pharmaceutical agent for the treatment of dyslipidemia and the metabolic syndrome. However, the chronic use of this peptide is potentially hampered by its inherent diabetogenic activity. Thyroid hormones (TH) influence energy expenditure, fat oxidation, and cholesterol metabolism. Although increased TH levels can improve serum lipid profile and reduce fat accumulation in the liver, these positive effects are counterbalanced by their potential harmful effects on the heart and bone. On the basis of these considerations, the global aim of this project was to characterize and perform an extensive in vivo pharmacological assessment of novel glucagon-T3 conjugates for efficient glucagon-mediated delivery of T3 selectively to the liver in order to reduce serum lipid levels and improve hepatic steatosis without causing adverse cardiovascular and glycemic effects. The researcher and collaborators demonstrated that chronic intervention with the novel conjugate corrected dyslipidemia, fatty liver, glucose intolerance and reduced body weight in several animal models metabolically compromised. In addition, they showed that treatment with the conjugate improved atherosclerosis in preclinical disease models and that intervention was safe, since no detrimental effects on the heart and bone were found after treatment with the conjugate, and the glycemic control was even improved. These findings suggest that the therapeutic utility of integrating these hormones into a single molecular entity offers unique potential for treatment of the metabolic syndrome and CVD.

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