Browsing by Author "Yang, Yan"

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    The effect of sugar-sweetened beverage consumption on childhood obesity - causal evidence
    (2016-05-18) Yang, Yan; Terza, Joseph V.; Courtemanche, Charles; Jung, Haeil; Mak, Henry Y.; Wu, Jisong
    Communities and States are increasingly targeting the consumption of sugar sweetened beverages (SSBs), especially soda, in their efforts to curb childhood obesity. However, the empirical evidence based on which policy makers design the relevant policies is not causally interpretable. In the present study, we suggest a modeling framework that can be used for making causal estimation and inference in the context of childhood obesity. This modeling framework is built upon the two-stage residual inclusion (2SRI) instrumental variables method and have two levels – level one models children’s lifestyle choices and level two models children’s energy balance which is assumed to be dependent on their lifestyle behaviors. We start with a simplified version of the model that includes only one policy, one lifestyle, one energy balance, and one observable control variable. We then extend this simple version to be a general one that accommodates multiple policy and lifestyle variables. The two versions of the model are 1) first estimated via the nonlinear least square (NLS) method (henceforth NLS-based 2SRI); and 2) then estimated via the maximum likelihood estimation (MLE) method (henceforth MLE-based 2SRI). Using simulated data, we show that 1) our proposed 2SRI method outperforms the conventional method that ignores the inherent nonlinearity [the linear instrumental variables (LIV) method] or the potential endogeneity [the nonlinear regression (NR) method] in obtaining the relevant estimators; and 2) the MLE-based 2SRI provides more efficient estimators (also consistent) compared to the NLS-based one. Real data analysis is conducted to illustrate the implementation of 2SRI method in practice using both NLS and MLE methods. However, due to data limitation, we are not able to draw any inference regarding the impacts of lifestyle, specifically SSB consumption, on childhood obesity. We are in the process of getting better data and, after doing so, we will replicate and extend the analyses conducted here. These analyses, we believe, will produce causally interpretable evidence of the effects of SSB consumption and other lifestyle choices on childhood obesity. The empirical analyses presented in this dissertation should, therefore, be viewed as an illustration of our newly proposed framework for causal estimation and inference.
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    Keap1 modulates the redox cycle and hepatocyte cell cycle in regenerating liver
    (Taylor & Francis, 2014-08-01) Hu, Min; Zou, Yuhong; Nambiar, Shashank Manohar; Lee, Joonyong; Yang, Yan; Dai, Guoli; Department of Biology, School of Science
    Keap1 negatively controls the activity of transcription factor Nrf2. This Keap1/Nrf2 pathway plays a critical role in combating oxidative stress. We aimed at determining whether and how Keap1 modulates the cell cycle of replicating hepatocytes during liver regeneration. Two-thirds partial hepatectomy (PH) was performed on wild-type mice and Keap1+/- (Keap1 knockdown) mice. We found that, following PH, Keap1 knockdown resulted in a delay in S-phase entry, disruption of S-phase progression, and loss of mitotic rhythm of replicating hepatocytes. These events are associated with dysregulation of c-Met, EGFR, Akt1, p70S6K, Cyclin A2, and Cyclin B1 in regenerating livers. Astonishingly, normal regenerating livers exhibited the redox fluctuation coupled with hepatocyte cell cycle progression, while keeping Nrf2 quiescent. Keap1 knockdown caused severe disruption in both the redox cycle and the cell cycle of replicating hepatocytes. Thus, we demonstrate that Keap1 is a potent regulator of hepatic redox cycle and hepatocyte cell cycle during liver regeneration.
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    Metabolic derivatives of alcohol and the molecular culprits of fibro-hepatocarcinogenesis: Allies or enemies?
    (BPG, 2016-01-07) Boye, Alex; Zou, Yu-Hong; Yang, Yan; Department of Biology, School of Science
    Chronic intake of alcohol undoubtedly overwhelms the structural and functional capacity of the liver by initiating complex pathological events characterized by steatosis, steatohepatitis, hepatic fibrosis and cirrhosis. Subsequently, these initial pathological events are sustained and ushered into a more complex and progressive liver disease, increasing the risk of fibro-hepatocarcinogenesis. These coordinated pathological events mainly result from buildup of toxic metabolic derivatives of alcohol including but not limited to acetaldehyde (AA), malondialdehyde (MDA), CYP2E1-generated reactive oxygen species, alcohol-induced gut-derived lipopolysaccharide, AA/MDA protein and DNA adducts. The metabolic derivatives of alcohol together with other comorbidity factors, including hepatitis B and C viral infections, dysregulated iron metabolism, abuse of antibiotics, schistosomiasis, toxic drug metabolites, autoimmune disease and other non-specific factors, have been shown to underlie liver diseases. In view of the multiple etiology of liver diseases, attempts to delineate the mechanism by which each etiological factor causes liver disease has always proved cumbersome if not impossible. In the case of alcoholic liver disease (ALD), it is even more cumbersome and complicated as a result of the many toxic metabolic derivatives of alcohol with their varying liver-specific toxicities. In spite of all these hurdles, researchers and experts in hepatology have strived to expand knowledge and scientific discourse, particularly on ALD and its associated complications through the medium of scientific research, reviews and commentaries. Nonetheless, the molecular mechanisms underpinning ALD, particularly those underlying toxic effects of metabolic derivatives of alcohol on parenchymal and non-parenchymal hepatic cells leading to increased risk of alcohol-induced fibro-hepatocarcinogenesis, are still incompletely elucidated. In this review, we examined published scientific findings on how alcohol and its metabolic derivatives mount cellular attack on each hepatic cell and the underlying molecular mechanisms leading to disruption of core hepatic homeostatic functions which probably set the stage for the initiation and progression of ALD to fibro-hepatocarcinogenesis. We also brought to sharp focus, the complex and integrative role of transforming growth factor beta/small mothers against decapentaplegic/plasminogen activator inhibitor-1 and the mitogen activated protein kinase signaling nexus as well as their cross-signaling with toll-like receptor-mediated gut-dependent signaling pathways implicated in ALD and fibro-hepatocarcinogenesis. Looking into the future, it is hoped that these deliberations may stimulate new research directions on this topic and shape not only therapeutic approaches but also models for studying ALD and fibro-hepatocarcinogenesis.
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    Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen
    (American Society for Pharmacology and Experimental Therapeutics, 2016-07) Rui, Wenjuan; Zou, Yuhong; Lee, Joonyong; Nambiar, Shashank Manohar; Lin, Jingmei; Zhang, Linjie; Yang, Yan; Dai, Guoli; Biology, School of Science
    Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates multiple biologic processes, including hepatic lipid metabolism. Estrogen exerts actions affecting energy homeostasis, including a liver fat-lowering effect. Increasing evidence indicates the crosstalk between these two molecules. The aim of this study was to evaluate whether Nrf2 modulates estrogen signaling in hepatic lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) was induced in wild-type and Nrf2-null mice fed a high-fat diet and the liver fat-lowering effect of exogenous estrogen was subsequently assessed. We found that exogenous estrogen eliminated 49% and 90% of hepatic triglycerides in wild-type and Nrf2-null mice with NAFLD, respectively. This observation demonstrates that Nrf2 signaling is antagonistic to estrogen signaling in hepatic fat metabolism; thus, Nrf2 absence results in striking amplification of the liver fat-lowering effect of estrogen. In addition, we found the association of trefoil factor 3 and fatty acid binding protein 5 with the liver fat-lowering effect of estrogen. In summary, we identified Nrf2 as a novel and potent inhibitor of estrogen signaling in hepatic lipid metabolism. Our finding may provide a potential strategy to treat NAFLD by dually targeting Nrf2 and estrogen signaling.