Honglin Sun

Bio: Honglin Sun is an academic researcher from Shanghai Jiao Tong University. The author has contributed to research in topics: Thermogenesis & Adipose tissue. The author has an hindex of 3, co-authored 6 publications receiving 23 citations.

Yin Yang 1 protein ameliorates diabetic nephropathy pathology through transcriptional repression of TGFβ1

Abstract: Transforming growth factor-β1 (TGFβ1) has been identified as a major pathogenic factor underlying the development of diabetic nephropathy (DN). However, the current strategy of antagonizing TGFβ1 has failed to demonstrate favorable outcomes in clinical trials. To identify a different therapeutic approach, we designed a mass spectrometry-based DNA-protein interaction screen to find transcriptional repressors that bind to the TGFB1 promoter and identified Yin Yang 1 (YY1) as a potent repressor of TGFB1. YY1 bound directly to TGFB1 promoter regions and repressed TGFB1 transcription in human renal mesangial cells. In mouse models, YY1 was elevated in mesangial cells during early diabetic renal lesions and decreased in later stages, and knockdown of renal YY1 aggravated, whereas overexpression of YY1 attenuated glomerulosclerosis. In addition, although their duration of diabetic course was comparable, patients with higher YY1 expression developed diabetic nephropathy more slowly compared to those who presented with lower YY1 expression. We found that a small molecule, eudesmin, suppressed TGFβ1 and other profibrotic factors by increasing YY1 expression in human renal mesangial cells and attenuated diabetic renal lesions in DN mouse models by increasing YY1 expression. These results suggest that YY1 is a potent transcriptional repressor of TGFB1 during the development of DN in diabetic mice and that small molecules targeting YY1 may serve as promising therapies for treating DN.

Indirubin, a small molecular deriving from connectivity map (CMAP) screening, ameliorates obesity-induced metabolic dysfunction by enhancing brown adipose thermogenesis and white adipose browning

Abstract: Obesity occurs when the body’s energy intake is constantly greater than its energy consumption and the pharmacological enhancing the activity of brown adipose tissue (BAT) and (or) browning of white adipose tissue (WAT) has been considered promising strategies to treat obesity. In this study, we took a multi-pronged approach to screen UCP1 activators, including in silico predictions, in vitro assays, as well as in vivo experiments. Base on Connectivity MAP (CMAP) screening, we obtained multiple drugs that possess a remarkably correlating gene expression pattern to that of enhancing activity in BAT and (or) sWAT signature. Particularly, we focused on a previously unreported drug-indirubin, a compound obtained from the Indigo plant, which is now mainly used for the treatment of chronic myelogenous leukemia (CML). In the current study, our results shown that indirubin could enhance the BAT activity, as evidenced by up-regulated Ucp1 expression and enhanced mitochondrial respiratory function in vitro cellular model. Furthermore, indirubin treatment restrained high-fat diet (HFD)-induced body weight gain, improved glucose homeostasis and ameliorated hepatic steatosis which were associated with the increase of energy expenditure in the mice model. Moreover, we revealed that indirubin treatment increased BAT activity by promoting thermogenesis and mitochondrial biogenesis in BAT and induced browning of subcutaneous inguinal white adipose tissue (sWAT) of mice under HFD. Besides, our results indicated that indirubin induced UCP1 expression in brown adipocytes, at least in part, via activation of PKA and p38MAPK signaling pathways. Our results clearly show that as an effective BAT (as well as beige cells) activator, indirubin may have a protective effect on the prevention and treatment of obesity and its complications.

Inhibition of XBP1s ubiquitination enhances its protein stability and improves glucose homeostasis.

Abstract: Background Hepatic ER stress is a risk factor of insulin resistance and type 2 diabetes. X-box binding protein 1 spliced (XBP1s), a transcription factor, plays a key role in ameliorating insulin resistance and maintaining glucose homeostasis. Unfortunately, the short half-life of the protein dampens its clinical application, and the specific site of lysine residue that could be ubiquitinated and involved in the degradation of XBP1s remains elusive. Methods and results Here, we identified K60 and K77 on XBP1s as two pivotal ubiquitin sites required for its proteasome-dependent degradation. We also constructed a double mutant form of XBP1s (K60/77R) and found that it showed higher capacity in resisting against ubiquitin-mediated protein degradation, increasing nuclear translocation, enhancing transcriptional activity, suppressing ER stress and promoting Foxo1 degradation, compared to that of wild type XBP1s (WT). Consistently, overexpression of the K60/77R XBP1s mutant in DIO mice increased the ability to reduce ER stress and decrease Foxo1 levels, thus contributed to maintaining glucose homeostasis. Conclusion Our results suggest that delaying the degradation of XBP1s by preventing ubiquitination might provide a strategic approach for reducing ER stress as an anti-diabetes therapy.

Theabrownin from Fu Brick Tea Exhibits the Thermogenic Function of Adipocytes in High-Fat-Diet-Induced Obesity.

Abstract: This study explored whether the antiobesity effect of theabrownin (TB) extracted from Fu brick tea (FBT) was associated with the activation of brown adipose tissue (BAT) or browning of the white adipose tissue (WAT) in mice fed a high-fat diet (HFD). Mice were divided into five groups, which received a normal diet, HFD, or HFD plus TB (200, 400, and 800 mg/kg), respectively. A 12-week administration of TB in a dose-dependent manner reduced the body weight and WAT weight and improved lipid and glucose disorders in the HFD-fed mice (p < 0.05). TB also promoted the expression of thermogenic and mitochondrial genes, whereas inflammation genes were reduced in interscapular BAT (iBAT), inguinal WAT (iWAT), and epididymis white adipose tissue (eWAT), accompanied by improvement in the intestinal homeostasis by improving SCFAs, especially butyric acid levels (p < 0.05), which was related to thermogenic and inflammatory factors of iBAT and iWAT. Mechanistically, TB was shown to efficiently promote thermogenesis by stimulating the AMPK-PGC1α pathway with an increase in uncoupling protein 1 (UCP1). Conclusively, these findings suggest that long-term consumption of TB can enhance BAT activity and WAT browning by activating the AMPK-PGC1α pathway and modulating SCFAs; meanwhile, SCFAs regulating TB improved inflammatory disorder in HFD-fed mice.

Sparcl1 promotes nonalcoholic steatohepatitis progression in mice through upregulation of CCL2

Abstract: Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of chronic liver disease ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms of NASH progression remain incompletely understood. White adipose tissue (WAT) has emerged as an important endocrine organ and contributes not only to the initial stage of NAFLD, but also to its severity. In the current study, through transcriptomic analysis we identified increased expression of Sparcl1, a secreted glycoprotein, in the WAT from NASH mice. Plasma Sparcl1 levels were similarly elevated and positively correlated with hepatic pathological features in NASH patients. Functional studies showed that both chronic injection of recombinant Sparcl1 protein and overexpression of Sparcl1 exaggerated hepatic inflammation and liver injury in mice. In contrast, genetic ablation of Sparcl1, knockdown of Sparcl1 in WAT, and treatment with a Sparcl1-neutralizing antibody dramatically alleviated diet-induced NASH pathogenesis. Mechanistically, Sparcl1 promoted the expression of C-C motif chemokine ligand 2 (CCL2) in hepatocytes through binding to Toll-like receptor 4 (TLR4) and activation of the NF-κB/p65 signaling pathway. Genetically or pharmacologically blocking the CCL2/CCR2 pathway attenuated the hepatic inflammatory response evoked by Sparcl1. Thus, our results demonstrated an important role for Sparcl1 in NASH progression, suggesting a potential target for therapeutic intervention.