Uncovering a novel role for FXR-SHP axis in liver physiology, diseases and beyond

Liver performs a multitude of functions ranging from detoxification, metabolism and digestion. To execute these tasks, one of the mechanisms that the liver utilizes is nuclear receptor signaling, which in turn can transcriptionally regulate gene networks. My doctoral thesis focuses on studying the role of two nuclear receptors, FXR and SHP in maintaining liver function. Farnesoid X Receptor (FXR) and Small Heterodimer Partner (SHP) are well-known regulators of glucose, fat and bile acid homeostasis. Here, I uncover novel roles for FXR-SHP axis not only in the liver but also in extrahepatic organs, like heart. In Chapter 2, I discuss how hepatic loss of FXR and SHP results in increased glycosylation of liver proteins and structural defects in Golgi apparatus, and ultimately liver cancer. Chapter 3 focuses on comprehending how FXR-SHP ablation results in increased drug metabolic capacity of the liver. Finally, chapter 4 discusses how liver dysfunction, caused by loss of FXR and SHP, can induce metabolic and functional defects in heart. Taken together, these projects will help understand some of the FXR and SHP transcriptional networks under different physiological and pathological contexts and may open avenues for pharmacological manipulation to treat various diseases

Uncovering a novel role for FXR-SHP axis in liver physiology, diseases and beyond

Liver performs a multitude of functions ranging from detoxification, metabolism and digestion. To execute these tasks, one of the mechanisms that the liver utilizes is nuclear receptor signaling, which in turn can transcriptionally regulate gene networks. My doctoral thesis focuses on studying the role of two nuclear receptors, FXR and SHP in maintaining liver function. Farnesoid X Receptor (FXR) and Small Heterodimer Partner (SHP) are well-known regulators of glucose, fat and bile acid homeostasis. Here, I uncover novel roles for FXR-SHP axis not only in the liver but also in extrahepatic organs, like heart. In Chapter 2, I discuss how hepatic loss of FXR and SHP results in increased glycosylation of liver proteins and structural defects in Golgi apparatus, and ultimately liver cancer. Chapter 3 focuses on comprehending how FXR-SHP ablation results in increased drug metabolic capacity of the liver. Finally, chapter 4 discusses how liver dysfunction, caused by loss of FXR and SHP, can induce metabolic and functional defects in heart. Taken together, these projects will help understand some of the FXR and SHP transcriptional networks under different physiological and pathological contexts and may open avenues for pharmacological manipulation to treat various diseases.U of I OnlyAuthor requested U of Illinois access only (OA after 2yrs) in Vireo ETD syste

Conceptions of happiness in relation to mindfulness

The preponderance of happiness research has centred on happiness's levels, predictors, and repercussions. Students’ everyday perceptions of happiness, on the other hand, have received a lot less attention. The study was conducted to investigate mindfulness in relation with various conceptions of happiness in academic setting. The sample of the study comprised 150 university students. The measures of the study included Mindfulness Attention Awareness Scale (Brown & Ryan, 2003), Hedonic and Eudaimonic Motives for Activities (Huta & Ryan, 2010), Fear of happiness Scale (Joshanloo & Weijers, 2014), Fragility of happiness scale (Joshanloo, Weijers, 2015), Externality of happiness scale (Joshanloo, 2017), Transformative Suffering scale (Joshanloo, 2014), Valuing Happiness Scale (Mauss, Tamir, Anderson & Savino, 2011), Inflexibility of Happiness Scale (Joshanloo, 2019), & Inclusive Happiness Scale (Joshanloo, 2019). The results of the study revealed that mindfulness was significantly and positively correlated with eudaimonism (r=0.351), transformative suffering (r=0.299), inclusive happiness (r=0.368) at p<0.01 and with valuing happiness (r=0.186) at p<0.05. It was seen that mindfulness was significantly and negatively correlated with externality of happiness (r= -0.491), fear of happiness (r= -0.408), fragility of happiness (r= -0.437), and inflexibility of happiness (r= -0.446) at p<0.01.&nbsp

Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart

Cardiac dysfunction in patients with liver cirrhosis is strongly associated with increased serum bile acid concentrations. Here we show that excess bile acids decrease fatty acid oxidation in cardiomyocytes and can cause heart dysfunction, a cardiac syndrome that we term cholecardia. Farnesoid X receptor; Small Heterodimer Partner double knockout mice, a model for bile acid overload, display cardiac hypertrophy, bradycardia, and exercise intolerance. In addition, double knockout mice exhibit an impaired cardiac response to catecholamine challenge. Consistent with this decreased cardiac function, we show that elevated serum bile acids reduce cardiac fatty acid oxidation both in vivo and ex vivo. We find that increased bile acid levels suppress expression of proliferator-activated receptor-γ coactivator 1α, a key regulator of fatty acid metabolism, and that proliferator-activated receptor-γ coactivator 1α overexpression in cardiac cells was able to rescue the bile acid-mediated reduction in fatty acid oxidation genes. Importantly, intestinal bile acid sequestration with cholestyramine was sufficient to reverse the observed heart dysfunction in the double knockout mice.ConclusionsDecreased proliferator-activated receptor-γ coactivator 1α expression contributes to the metabolic dysfunction in cholecardia so that reducing serum bile acid concentrations may be beneficial against the metabolic and pathological changes in the heart. (Hepatology 2017;65:189-201)

Nuclear receptors FXR and SHP regulate protein N-glycan modifications in the liver

Nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP) are key regulators of metabolism. Here, we report a previously unknown function for the hepatic FXR-SHP axis in controlling protein N-linked glycosylation. Transcriptome analysis in liver-specific Fxr-Shp double knockout (LDKO) livers revealed induction of genes encoding enzymes in the N-glycosylation pathway, including Mgat5, Fut8, St3gal6, and St6gal1. FXR activation suppressed Mgat5, while Shp deletion induced St3gal6 and St6gal1. Increased percentages of core-fucosylated and triantennary glycan moieties were seen in LDKO livers, and proteins with the "hyperglycoforms" preferentially localized to exosomes and lysosomes. This up-regulation of N-glycosylation machinery was specific to the Golgi apparatus and not the endoplasmic reticulum. The increased glycan complexity in the LDKO correlated well with dilated unstacked Golgi ribbons and alterations in the secretion of albumin, cholesterol, and triglycerides. Our findings demonstrate a role for the FXR-SHP axis in maintaining glycoprotein diversity in the liver