TY - JOUR A1 - Tian, Mei A1 - Reichetzeder, Christoph A1 - Li, Jian A1 - Hocher, Berthold T1 - Low birth weight, a risk factor for diseases in later life, is a surrogate of insulin resistance at birth JF - Journal of hypertension N2 - Low birth weight (LBW) is associated with diseases in adulthood. The birthweight attributed risk is independent of confounding such as gestational age, sex of the newborn but also social factors. The birthweight attributed risk for diseases in later life holds for the whole spectrum of birthweight. This raises the question what pathophysiological principle is actually behind the association. In this review, we provide evidence that LBW is a surrogate of insulin resistance. Insulin resistance has been identified as a key factor leading to type 2 diabetes, cardiovascular disease as well as kidney diseases. We first provide evidence linking LBW to insulin resistance during intrauterine life. This might be caused by both genetic (genetic variations of genes controlling glucose homeostasis) and/or environmental factors (due to alterations of macronutrition and micronutrition of the mother during pregnancy, but also effects of paternal nutrition prior to conception) leading via epigenetic modifications to early life insulin resistance and alterations of intrauterine growth, as insulin is a growth factor in early life. LBW is rather a surrogate of insulin resistance in early life - either due to inborn genetic or environmental reasons - rather than a player on its own. KW - epigenetics KW - fetal programing KW - genetics KW - insulin resistance KW - low birth weight Y1 - 2019 U6 - https://doi.org/10.1097/HJH.0000000000002156 SN - 0263-6352 SN - 1473-5598 VL - 37 IS - 11 SP - 2123 EP - 2134 PB - Kluwer CY - Philadelphia ER - TY - JOUR A1 - Krstic, Jelena A1 - Reinisch, Isabel A1 - Schupp, Michael A1 - Schulz, Tim Julius A1 - Prokesch, Andreas T1 - p53 functions in adipose tissue metabolism and homeostasis JF - International journal of molecular sciences N2 - As a tumor suppressor and the most frequently mutated gene in cancer, p53 is among the best-described molecules in medical research. As cancer is in most cases an age-related disease, it seems paradoxical that p53 is so strongly conserved from early multicellular organisms to humans. A function not directly related to tumor suppression, such as the regulation of metabolism in nontransformed cells, could explain this selective pressure. While this role of p53 in cellular metabolism is gradually emerging, it is imperative to dissect the tissue-and cell-specific actions of p53 and its downstream signaling pathways. In this review, we focus on studies reporting p53's impact on adipocyte development, function, and maintenance, as well as the causes and consequences of altered p53 levels in white and brown adipose tissue (AT) with respect to systemic energy homeostasis. While whole body p53 knockout mice gain less weight and fat mass under a high-fat diet owing to increased energy expenditure, modifying p53 expression specifically in adipocytes yields more refined insights: (1) p53 is a negative regulator of in vitro adipogenesis; (2) p53 levels in white AT are increased in diet-induced and genetic obesity mouse models and in obese humans; (3) functionally, elevated p53 in white AT increases senescence and chronic inflammation, aggravating systemic insulin resistance; (4) p53 is not required for normal development of brown AT; and (5) when p53 is activated in brown AT in mice fed a high-fat diet, it increases brown AT temperature and brown AT marker gene expression, thereby contributing to reduced fat mass accumulation. In addition, p53 is increasingly being recognized as crucial player in nutrient sensing pathways. Hence, despite existence of contradictory findings and a varying density of evidence, several functions of p53 in adipocytes and ATs have been emerging, positioning p53 as an essential regulatory hub in ATs. Future studies need to make use of more sophisticated in vivo model systems and should identify an AT-specific set of p53 target genes and downstream pathways upon different (nutrient) challenges to identify novel therapeutic targets to curb metabolic diseases KW - p53 KW - adipose tissue KW - metabolic syndrome KW - obesity KW - adipogenesis KW - insulin resistance Y1 - 2018 U6 - https://doi.org/10.3390/ijms19092622 SN - 1422-0067 VL - 19 IS - 9 PB - MDPI CY - Basel ER - TY - JOUR A1 - Krstic, Jelena A1 - Galhuber, Markus A1 - Schulz, Tim Julius A1 - Schupp, Michael A1 - Prokesch, Andreas T1 - p53 as a dichotomous regulator of liver disease BT - the dose makes the medicine JF - International journal of molecular sciences N2 - Lifestyle-related disorders, such as the metabolic syndrome, have become a primary risk factor for the development of liver pathologies that can progress from hepatic steatosis, hepatic insulin resistance, steatohepatitis, fibrosis and cirrhosis, to the most severe condition of hepatocellular carcinoma (HCC). While the prevalence of liver pathologies is steadily increasing in modern societies, there are currently no approved drugs other than chemotherapeutic intervention in late stage HCC. Hence, there is a pressing need to identify and investigate causative molecular pathways that can yield new therapeutic avenues. The transcription factor p53 is well established as a tumor suppressor and has recently been described as a central metabolic player both in physiological and pathological settings. Given that liver is a dynamic tissue with direct exposition to ingested nutrients, hepatic p53, by integrating cellular stress response, metabolism and cell cycle regulation, has emerged as an important regulator of liver homeostasis and dysfunction. The underlying evidence is reviewed herein, with a focus on clinical data and animal studies that highlight a direct influence of p53 activity on different stages of liver diseases. Based on current literature showing that activation of p53 signaling can either attenuate or fuel liver disease, we herein discuss the hypothesis that, while hyper-activation or loss of function can cause disease, moderate induction of hepatic p53 within physiological margins could be beneficial in the prevention and treatment of liver pathologies. Hence, stimuli that lead to a moderate and temporary p53 activation could present new therapeutic approaches through several entry points in the cascade from hepatic steatosis to HCC. KW - p53 KW - liver disease KW - insulin resistance KW - non-alcoholic fatty liver disease KW - non-alcoholic steatohepatitis KW - hepatocellular carcinoma KW - liver regeneration KW - mouse models Y1 - 2018 U6 - https://doi.org/10.3390/ijms19030921 SN - 1422-0067 VL - 19 IS - 3 PB - MDPI CY - Basel ER - TY - JOUR A1 - Kleuser, Burkhard T1 - Divergent role of sphingosine 1-phosphate in liver health and disease JF - International journal of molecular sciences N2 - Two decades ago, sphingosine 1-phosphate (S1P) was discovered as a novel bioactive molecule that regulates a variety of cellular functions. The plethora of S1P-mediated effects is due to the fact that the sphingolipid not only modulates intracellular functions but also acts as a ligand of G protein-coupled receptors after secretion into the extracellular environment. In the plasma, S1P is found in high concentrations, modulating immune cell trafficking and vascular endothelial integrity. The liver is engaged in modulating the plasma S1P content, as it produces apolipoprotein M, which is a chaperone for the S1P transport. Moreover, the liver plays a substantial role in glucose and lipid homeostasis. A dysfunction of glucose and lipid metabolism is connected with the development of liver diseases such as hepatic insulin resistance, non-alcoholic fatty liver disease, or liver fibrosis. Recent studies indicate that S1P is involved in liver pathophysiology and contributes to the development of liver diseases. In this review, the current state of knowledge about S1P and its signaling in the liver is summarized with a specific focus on the dysregulation of S1P signaling in obesity-mediated liver diseases. Thus, the modulation of S1P signaling can be considered as a potential therapeutic target for the treatment of hepatic diseases. KW - sphingolipids KW - sphingosine kinase KW - fibrosis KW - non-alcoholic fatty liver disease KW - insulin resistance KW - liver fibrosis Y1 - 2018 U6 - https://doi.org/10.3390/ijms19030722 SN - 1422-0067 VL - 19 IS - 3 PB - MDPI CY - Basel ER -