👤 Christopher Koh

Arteriovenous-lymphatic endothelial cell fates are specified by the master regulators, namely, Notch, COUP-TFII, and Prox1. Whereas Notch is expressed in the arteries and COUP-TFII in the veins, the lymphatics express all 3 cell fate regulators. Previous studies show that lymphatic endothelial cell (LEC) fate is highly plastic and reversible, raising a new concept that all 3 endothelial cell fates may co-reside in LECs and a subtle alteration can result in a reprogramming of LEC fate. We provide a molecular basis verifying this concept by identifying a cross-control mechanism among these cell fate regulators. We found that Notch signal down-regulates Prox1 and COUP-TFII through Hey1 and Hey2 and that activated Notch receptor suppresses the lymphatic phenotypes and induces the arterial cell fate. On the contrary, Prox1 and COUP-TFII attenuate vascular endothelial growth factor signaling, known to induce Notch, by repressing vascular endothelial growth factor receptor-2 and neuropilin-1. We show that previously reported podoplanin-based LEC heterogeneity is associated with differential expression of Notch1 in human cutaneous lymphatics. We propose that the expression of the 3 cell fate regulators is controlled by an exquisite feedback mechanism working in LECs and that LEC fate is a consequence of the Prox1-directed lymphatic equilibrium among the cell fate regulators. Show less

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Recently, abnormal activation of the Wnt pathway has been found to be involved in the carcinogenesis of HCC. However, the relationship between genetic changes in the Wnt pathway-associated genes and its protein expression has not been studied in patients with HCC and cirrhotic nodules. The purpose of this study is to explore the contribution of inappropriate activation of the Wnt pathway in liver carcinogenesis. Somatic mutation in exons 3-5 of AXIN1 and exon 3 of beta-catenin were analyzed by direct sequencing and expression of axin and beta-catenin proteins by immunohistochemistry in a series of 36 patients with HCC and cirrhosis. The AXIN1 and beta-catenin gene mutations were observed in 25% (9/36) and 2.8% (1/36) of HCCs, respectively. All mutations detected in AXIN1 and beta-catenin genes were missense point mutations. Abnormal nuclear expression of beta-catenin was observed in 11 of 36 cases of HCCs (30.6%), but not in cirrhotic nodules. Reduced or absent expression of axin was seen in 24 of 36 HCCs (66.7%). The abnormal expression of beta-catenin and axin proteins was closely correlated with mutations of AXIN1 and beta-catenin (P < 0.0001 and P = 0.008, respectively). These data suggest that mutation of AXIN1 gene is a frequent and late event for HCC associated with cirrhosis, and is correlated significantly with abnormal expression of axin and beta-catenin. Therefore, activation of Wnt signaling through AXIN1 rather than beta-catenin mutation might play an important role in liver carcinogenesis. Show less

The purpose of this study was to compare low-fat (LF) meal and high-fat (HF) meal on the postprandial lipemic responses according to the -1131T>C polymorphism of the APOA5 gene in a population usually consuming a LF diet and having a high frequency of the variant allele at the APOA5 -1131T>C SNP. This study was conducted using a cross-over design and 49 non-obese healthy men (42.8 +/- 0.7 yrs, 23.9 +/- 0.25 kg/m(2)) participated in the meal tolerance test. They were randomly assigned to consume one of two types of experimental enteral formulae (LF vs HF) with a seven-day interval. Blood samples were collected at 0, 2, 3, 4 and 6h after ingestion and analyzed for total and chylomicron TG, glucose, insulin and free fatty acid. No differences were found in anthropometic parameter, calorie and macronutrient intakes and total energy expenditure between TT (n = 23) and TC + CC (n = 26) men. Fasting total TG were higher in TC + CC men than TT men, but fasting chylomicron TG were not significantly different between TT men and C carriers, TT subjects had no significant differences in postprandial responses of total TG and chylomicron TG and postprandial mean changes of chylomicron TG between LF and HF meal. On the other hand, C carriers had delayed peak time of total TG compared to TT subject and higher postprandial response and mean changes of chylomicron TG at HF meal compared to LF meal. The capacity to clear chylomicron-TG or hydrolyze TG might become a rate-limiting factor on HF diet in TC + CC men resulting in higher postprandial triglyceridemia. Therefore, HF diet for C carriers of the APOA5 gene may be one of important CVD risk factors. Show less