Stanford Advisors

All Publications

  • Targeting phospholipid remodeling pathway improves insulin resistance in diabetic mouse models FASEB JOURNAL Tian, Y., Lu, W., Shi, R., Mcguffee, R., Lee, R., Ford, D. A., Wang, B. 2023; 37 (11): e23251


    Previous studies have revealed that membrane phospholipid composition controlled by lysophosphatidylcholine acyltransferase 3 (LPCAT3) is involved in the development of insulin resistance in type 2 diabetes. In this study, we aimed to investigate the therapeutic potential of targeting Lpcat3 in the treatment of insulin resistance in diabetic mouse models. Lpcat3 expression was suppressed in the whole body by antisense oligonucleotides (ASO) injection or in the liver by adeno-associated virus (AAV)-encoded Cre in high-fat diet (HFD)-induced and genetic ob/ob type 2 diabetic mouse models. Glucose tolerance test (GTT), insulin tolerance test (ITT), fasting blood glucose, and insulin levels were used to assess insulin sensitivity. Lipid levels in the liver and serum were measured. The expression of genes involved in de novo lipogenesis was analyzed by real-time RT-PCR. Metabolic rates were measured by indirect calorimetry using the Comprehensive Lab Animal Monitoring System (CLAMS). Our data demonstrate that acute knockout of hepatic Lpcat3 by AAV-Cre improves both hyperglycemia and hypertriglyceridemia in HFD-fed mice. Similarly, whole-body ablation of Lpcat3 by ASO administration improves obesity and insulin resistance in both HFD-fed and ob/ob mice. These findings demonstrate that targeting LPCAT3 could be a novel therapy for insulin resistance.

    View details for DOI 10.1096/fj.202301122RR

    View details for Web of Science ID 001091922000008

    View details for PubMedID 37823674

    View details for PubMedCentralID PMC10575708

  • Unraveling the pathogenesis of non-alcoholic fatty liver diseases through genome-wide association studies JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY Tian, Y., Wang, B. 2023; 38 (11): 1877-1885


    Non-alcoholic fatty liver disease (NAFLD) is a significant health burden around the world, affecting approximately 25% of the population. Recent advances in human genetic databases have allowed for the identification of various single nucleotide polymorphisms associated with NAFLD-related traits. Investigating the functions of these genetic factors provides insight into the pathogenesis of NAFLD and potentially identifies novel therapeutic targets for NAFLD. In this review, we summarized current research on genes with NAFLD-associated mutations, highlighting phospholipid remodeling and spatially clustered loci as common pathological and genetic features of these mutations. These features suggest a complex yet intriguing mechanism of dissociated steatosis and insulin resistance, which is observed in a subset of patients and may lead to more precise therapy against NAFLD in the future.

    View details for DOI 10.1111/jgh.16330

    View details for Web of Science ID 001051040100001

    View details for PubMedID 37592846

    View details for PubMedCentralID PMC10693931

  • Hepatic Phospholipid Remodeling Modulates Insulin Sensitivity and Systemic Metabolism. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Tian, Y., Mehta, K., Jellinek, M. J., Sun, H., Lu, W., Shi, R., Ingram, K., Friedline, R. H., Kim, J. K., Kemper, J. K., Ford, D. A., Zhang, K., Wang, B. 2023; 10 (18): e2300416


    The liver plays a central role in regulating glucose and lipid metabolism. Aberrant insulin action in the liver is a major driver of selective insulin resistance, in which insulin fails to suppress glucose production but continues to activate lipogenesis in the liver, resulting in hyperglycemia and hypertriglyceridemia. The underlying mechanisms of selective insulin resistance are not fully understood. Here It is shown that hepatic membrane phospholipid composition controlled by lysophosphatidylcholine acyltransferase 3 (LPCAT3) regulates insulin signaling and systemic glucose and lipid metabolism. Hyperinsulinemia induced by high-fat diet (HFD) feeding augments hepatic Lpcat3 expression and membrane unsaturation. Loss of Lpcat3 in the liver improves insulin resistance and blunts lipogenesis in both HFD-fed and genetic ob/ob mouse models. Mechanistically, Lpcat3 deficiency directly facilitates insulin receptor endocytosis, signal transduction, and hepatic glucose production suppression and indirectly enhances fibroblast growth factor 21 (FGF21) secretion, energy expenditure, and glucose uptake in adipose tissue. These findings identify hepatic LPCAT3 and membrane phospholipid composition as a novel regulator of insulin sensitivity and provide insights into the pathogenesis of selective insulin resistance.

    View details for DOI 10.1002/advs.202300416

    View details for PubMedID 37088778

    View details for PubMedCentralID PMC10288282

  • Intestinal SEC16B modulates obesity by regulating chylomicron metabolism. Molecular metabolism Shi, R., Lu, W., Tian, Y., Wang, B. 2023; 70: 101693


    Genome-wide association studies (GWAS) have identified genetic variants in SEC16 homolog B (SEC16B) locus to be associated with obesity and body mass index (BMI) in various populations. SEC16B encodes a scaffold protein located at endoplasmic reticulum (ER) exit sites that is implicated to participate in the trafficking of COPII vesicles in mammalian cells. However, the function of SEC16B in vivo, especially in lipid metabolism, has not been investigated.We generated Sec16b intestinal knockout (IKO) mice and assessed the impact of its deficiency on high-fat diet (HFD) induced obesity and lipid absorption in both male and female mice. We examined lipid absorption in vivo by acute oil challenge and fasting/HFD refeeding. Biochemical analyses and imaging studies were performed to understand the underlying mechanisms.Our results showed that Sec16b intestinal knockout (IKO) mice, especially female mice, were protected from HFD-induced obesity. Loss of Sec16b in intestine dramatically reduced postprandial serum triglyceride output upon intragastric lipid load or during overnight fasting and HFD refeeding. Further studies showed that intestinal Sec16b deficiency impaired apoB lipidation and chylomicron secretion.Our studies demonstrated that intestinal SEC16B is required for dietary lipid absorption in mice. These results revealed that SEC16B plays important roles in chylomicron metabolism, which may shed light on the association between variants in SEC16B and obesity in human.

    View details for DOI 10.1016/j.molmet.2023.101693

    View details for PubMedID 36796587

    View details for PubMedCentralID PMC9976576

  • Membrane phospholipid remodeling modulates nonalcoholic steatohepatitis progression by regulating mitochondrial homeostasis. Hepatology (Baltimore, Md.) Tian, Y., Jellinek, M. J., Mehta, K., Seok, S. M., Kuo, S. H., Lu, W., Shi, R., Lee, R., Lau, G. W., Kemper, J. K., Zhang, K., Ford, D. A., Wang, B. 2023


    NASH, characterized by inflammation and fibrosis, is emerging as a leading etiology of HCC. Lipidomics analyses in the liver have shown that the levels of polyunsaturated phosphatidylcholine (PC) are decreased in patients with NASH, but the roles of membrane PC composition in the pathogenesis of NASH have not been investigated. Lysophosphatidylcholine acyltransferase 3 (LPCAT3), a phospholipid (PL) remodeling enzyme that produces polyunsaturated PLs, is a major determinant of membrane PC content in the liver.The expression of LPCAT3 and the correlation between its expression and NASH severity were analyzed in human patient samples. We examined the effect of Lpcat3 deficiency on NASH progression using Lpcat3 liver-specific knockout (LKO) mice. RNA sequencing, lipidomics, and metabolomics were performed in liver samples. Primary hepatocytes and hepatic cell lines were used for in vitro analyses. We showed that LPCAT3 was dramatically suppressed in human NASH livers, and its expression was inversely correlated with NAFLD activity score and fibrosis stage. Loss of Lpcat3 in mouse liver promotes both spontaneous and diet-induced NASH/HCC. Mechanistically, Lpcat3 deficiency enhances reactive oxygen species production due to impaired mitochondrial homeostasis. Loss of Lpcat3 increases inner mitochondrial membrane PL saturation and elevates stress-induced autophagy, resulting in reduced mitochondrial content and increased fragmentation. Furthermore, overexpression of Lpcat3 in the liver ameliorates inflammation and fibrosis of NASH.These results demonstrate that membrane PL composition modulates the progression of NASH and that manipulating LPCAT3 expression could be an effective therapeutic for NASH.

    View details for DOI 10.1097/HEP.0000000000000375

    View details for PubMedID 36999536

    View details for PubMedCentralID PMC10544743

  • De novo design of an intercellular signaling toolbox for multi-channel cell-cell communication and biological computation. Nature communications Du, P., Zhao, H., Zhang, H., Wang, R., Huang, J., Tian, Y., Luo, X., Luo, X., Wang, M., Xiang, Y., Qian, L., Chen, Y., Tao, Y., Lou, C. 2020; 11 (1): 4226


    Intercellular signaling is indispensable for single cells to form complex biological structures, such as biofilms, tissues and organs. The genetic tools available for engineering intercellular signaling, however, are quite limited. Here we exploit the chemical diversity of biological small molecules to de novo design a genetic toolbox for high-performance, multi-channel cell-cell communications and biological computations. By biosynthetic pathway design for signal molecules, rational engineering of sensing promoters and directed evolution of sensing transcription factors, we obtain six cell-cell signaling channels in bacteria with orthogonality far exceeding the conventional quorum sensing systems and successfully transfer some of them into yeast and human cells. For demonstration, they are applied in cell consortia to generate bacterial colony-patterns using up to four signaling channels simultaneously and to implement distributed bio-computation containing seven different strains as basic units. This intercellular signaling toolbox paves the way for engineering complex multicellularity including artificial ecosystems and smart tissues.

    View details for DOI 10.1038/s41467-020-17993-w

    View details for PubMedID 32839450

    View details for PubMedCentralID PMC7445162