Biology subjects

Chuang, L.-M.

Publications and source records attributed to Chuang, L.-M..

5 recordsLinked to original sources

bioRxiv2024

Identification of PTGR2 inhibitors as a new therapy for diabetes and obesity

Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) is a master transcriptional regulator of systemic insulin sensitivity and energy balance. The anti-diabetic drug thiazolidinediones (TZDs) are potent synthetic PPAR{gamma} ligands with undesirable side effects, including obesity, fluid retention, and osteoporosis. 15-keto prostaglandin E2 (15-keto-PGE2) is an endogenous PPAR{gamma} ligand metabolized by prostaglandin reductase 2 (PTGR2). Here, we confirmed that 15-keto-PGE2 binds and activates PPAR{gamma} via covalent binding. In patients with type 2 diabetes and obese mice, serum 15-keto-PGE2 levels were decreased. Administration of 15-keto-PGE2 improves glucose homeostasis and prevented diet-induced obesity in mice. Either genetic inhibition of PTGR2 or PTGR2 inhibitor BPRPT0245 protected mice from diet-induced obesity, insulin resistance, and hepatic steatosis without fluid retention and osteoporosis. In conclusion, inhibition of PTGR2 is a new therapeutic approach to treat diabetes and obesity through increasing endogenous PPAR{gamma} ligands without side effects of synthetic PPAR{gamma} ligands TZDs.

physiology↗

bioRxiv2021

Whole genome sequence analysis of blood lipid levels in >66,000 individuals

Plasma lipids are heritable modifiable causal factors for coronary artery disease, the leading cause of death globally. Despite the well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing, partly due to limited sample sizes, ancestral diversity, and interpretation of potential clinical significance. Increasingly larger whole genome sequence datasets with plasma lipids coupled with methodologic advances enable us to more fully catalog the allelic spectrum for lipids. Here, among 66,329 ancestrally diverse (56% non-European ancestry) participants, we associate 428M variants from deep-coverage whole genome sequences with plasma lipids. Approximately 400M of these variants were not studied in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with plasma lipids through analysis of common and rare coding variants. We additionally discover several significantly associated rare non-coding variants largely at Mendelian lipid genes. Notably, we detect rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for plasma lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

genetics↗

bioRxiv2021

Dynamin-2 Phosphorylation as A Critical Regulatory Target of Bin1 and GSK3α for Endocytosis in Muscle

Tight regulation of endocytosis ensures accurate control of cellular signaling and membrane dynamics, which are crucial for tissue morphogenesis and functions. Mutations of Bin1 and dynamin-2 (Dyn2), proteins that generate membrane curvature and sever endocytic invaginations, respectively, cause progressive hereditary myopathy. Here, we show that Bin1 inhibits Dyn2 via direct interaction of its SRC Homology 3 (SH3) domain with the proline-rich domain (PRD) of Dyn2. Phosphorylation of S848 of Dyn2 by GSK3, a kinase downstream of insulin signaling, relieves Dyn2 from the inhibition of Bin1 and promotes endocytosis in muscle. Mutations of Bin1 associated with centronuclear myopathy disrupt its inhibition of Dyn2, thereby exaggerating Dyn2 fission activity and causing excessive fragmentation of T-tubules in the muscle cells. Our work reveals how Bin1-Dyn2 interaction fine-tunes membrane remodeling at the molecular level, and lay the foundation for future exploration of endocytic regulation and hereditary muscle diseases.

cell biology↗

bioRxiv2021

Insulin Signaling Attenuates GLUT4 Endocytosis in Muscle Cells via GSK3a-Dyn2-Bin1 Interplay

Insulin-induced translocation of glucose transporter 4 (GLUT4) to the plasma membrane of skeletal muscle is critical for postprandial glucose uptake; however, whether the internalization of GLUT4 into cells is also regulated by insulin signaling remains unclear. Here, we discover that the activity of dynamin-2 (Dyn2), pivotal GTPase catalyzing GLUT4 internalization, is regulated by insulin signaling in muscle cells. The membrane fission activity of Dyn2 is inhibited in muscle cells through binding with the SH3 domain-containing protein Bin1. Phosphorylation of Serine848 on Dyn2 by GSK3 or the mutations of Bin1-SH3 in patients with centronuclear myopathy, elevate the activity of Dyn2 due to reduced binding affinity toward Bin1. The augmented Dyn2 fission activity in muscle cells leads to GLUT4 internalization and Bin1-tubule vesiculation. Together, our findings reveal a new role of insulin signaling in glucose metabolism and muscle physiology via attenuating Dyn2 activity thus regulating GLUT4 endocytosis in muscle cell.

cell biology↗

bioRxiv2019

Identification of type 2 diabetes loci in 433,540 East Asian individuals

Meta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.\n\nType 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic {beta} cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

genetics↗