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Regulation of Immunometabolic Processes in Atherosclerosis and Nonalcoholic Fatty Liver Disease by Liver Receptor Homolog 1


Stein, Sokrates. Regulation of Immunometabolic Processes in Atherosclerosis and Nonalcoholic Fatty Liver Disease by Liver Receptor Homolog 1. 2018, University of Zurich, Faculty of Medicine.

Abstract

The metabolic syndrome is a cluster of interconnected diseases, including insulin resistance, obesity, hypertension, and dyslipidemias, and it is tightly associated with the development of atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes mellitus. NALFD is one of the primary causes of liver disease in the world and it is strongly associated with cardiovascular risk factors. The disease encompasses different stages of liver disorders, starting with the excessive massive accumulation of hepatic triglycerides. Atherosclerosis is the primary cause of myocardial infarction and stroke, two of the leading causes of mortality in the world. One hallmark of the disease is the excessive accumulation of cholesterol in monocyte-derived macrophages within atherosclerotic lesions. Both atherosclerosis and NAFLD are immunometabolic diseases, i.e. chronic diseases that are affected by both metabolic and immunological triggers and signaling networks.

The signaling cascades that are activated by inflammatory and metabolic mediators converge at key transcriptional regulators, which in turn coordinate the expression of specific target genes. Together with colleagues I demonstrated that the nuclear receptor homolog-1 (LRH-1) affects the development of both atherosclerosis and NAFLD by regulating immunometabolic processes. We showed that atherosclerosis-prone mice carrying a mutation that abolishes the SUMOylation of the nuclear receptor (i.e. LRH-1 K289R) are significantly protected from atherosclerosis development in mice challenged with a high-cholesterol diet. This atheroprotection was regulated by the corepressor prospero-related homeobox 1 (PROX1), which normally transrepresses the transcription of genes involved in hepatic reverse cholesterol transport. On the other side, we showed that this same LRH-1 mutation promotes the development of NAFLD and early signs of steatohepatitis if mice are challenged with a lipogenic high-fat high-sucrose diet. These studies highlighted that a single posttranslational modification of a specific residue of a transcriptional regulator is sufficient to modulate the function of the protein and the corresponding cellular and metabolic processes, which consequently can affect the development of these complex chronic diseases.

In this habilitation I will summarize these two major studies as well as other work that underline the crucial function that this nuclear receptor exerts in the liver and macrophages under different genetic backgrounds and dietary challenges. These studies are of high translational potential given the availability of specific LRH-1 agonists and antagonists that could potentially be used to modulate the development and/or progression of these chronic diseases.

Abstract

The metabolic syndrome is a cluster of interconnected diseases, including insulin resistance, obesity, hypertension, and dyslipidemias, and it is tightly associated with the development of atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes mellitus. NALFD is one of the primary causes of liver disease in the world and it is strongly associated with cardiovascular risk factors. The disease encompasses different stages of liver disorders, starting with the excessive massive accumulation of hepatic triglycerides. Atherosclerosis is the primary cause of myocardial infarction and stroke, two of the leading causes of mortality in the world. One hallmark of the disease is the excessive accumulation of cholesterol in monocyte-derived macrophages within atherosclerotic lesions. Both atherosclerosis and NAFLD are immunometabolic diseases, i.e. chronic diseases that are affected by both metabolic and immunological triggers and signaling networks.

The signaling cascades that are activated by inflammatory and metabolic mediators converge at key transcriptional regulators, which in turn coordinate the expression of specific target genes. Together with colleagues I demonstrated that the nuclear receptor homolog-1 (LRH-1) affects the development of both atherosclerosis and NAFLD by regulating immunometabolic processes. We showed that atherosclerosis-prone mice carrying a mutation that abolishes the SUMOylation of the nuclear receptor (i.e. LRH-1 K289R) are significantly protected from atherosclerosis development in mice challenged with a high-cholesterol diet. This atheroprotection was regulated by the corepressor prospero-related homeobox 1 (PROX1), which normally transrepresses the transcription of genes involved in hepatic reverse cholesterol transport. On the other side, we showed that this same LRH-1 mutation promotes the development of NAFLD and early signs of steatohepatitis if mice are challenged with a lipogenic high-fat high-sucrose diet. These studies highlighted that a single posttranslational modification of a specific residue of a transcriptional regulator is sufficient to modulate the function of the protein and the corresponding cellular and metabolic processes, which consequently can affect the development of these complex chronic diseases.

In this habilitation I will summarize these two major studies as well as other work that underline the crucial function that this nuclear receptor exerts in the liver and macrophages under different genetic backgrounds and dietary challenges. These studies are of high translational potential given the availability of specific LRH-1 agonists and antagonists that could potentially be used to modulate the development and/or progression of these chronic diseases.

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Additional indexing

Item Type:Habilitation (monographical)
Communities & Collections:04 Faculty of Medicine > Center for Molecular Cardiology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2018
Deposited On:04 Oct 2019 13:34
Last Modified:07 Apr 2020 07:22
Number of Pages:95
OA Status:Closed

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