Discovery of an insulin-induced gene binding compound that ameliorates nonalcoholic steatohepatitis by inhibiting sterol regulatory element-binding protein-mediated lipogenesis.

Background And Aims: NASH is associated with high levels of cholesterol and triglyceride (TG) in the liver; however, there is still no approved pharmacological therapy. Synthesis of cholesterol and TG is controlled by sterol regulatory element-binding protein (SREBP), which is found to be abnormally activated in NASH patients. We aim to discover small molecules for treating NASH by inhibiting the SREBP pathway.

The GARP Complex Is Involved in Intracellular Cholesterol Transport via Targeting NPC2 to Lysosomes.

Proper intracellular cholesterol trafficking is critical for cellular function. Two lysosome-resident proteins, NPC1 and NPC2, mediate the egress of low-density lipoprotein-derived cholesterol from lysosomes. However, other proteins involved in this process remain largely unknown.

Identification and characterization of NPC1L1 variants in Uygur and Kazakh with extreme low-density lipoprotein cholesterol.

Background: Plasma levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor for cardiovascular disease and are influenced by both heredity and dietary habits. The Niemann-Pick C1 like 1 (NPC1L1) protein mediates efficient dietary cholesterol absorption and contributes to variations in human LDL-C levels.

Methods: In the present study, using high throughput sequencing we identified three non-synonymous (NS) variations and 64 synonymous variations in the NPC1L1 gene from subsets of Chinese Han, Uygur and Kazakh populations with high or low LDL-C.

Numb directs the subcellular localization of EAAT3 through binding the YxNxxF motif.

Excitatory amino acid transporter type 3 (EAAT3, also known as SLC1A1) is a high-affinity, Na(+)-dependent glutamate carrier that localizes primarily within the cell and at the apical plasma membrane. Although previous studies have reported proteins and sequence regions involved in EAAT3 trafficking, the detailed molecular mechanism by which EAAT3 is distributed to the correct location still remains elusive. Here, we identify that the YVNGGF sequence in the C-terminus of EAAT3 is responsible for its intracellular localization and apical sorting in rat hepatoma cells CRL1601 and Madin-Darby canine kidney (MDCK) cells, respectively.

Forward genetic screening for regulators involved in cholesterol synthesis using validation-based insertional mutagenesis.

Somatic cell genetics is a powerful approach for unraveling the regulatory mechanism of cholesterol metabolism. However, it is difficult to identify the mutant gene(s) due to cells are usually mutagenized chemically or physically. To identify important genes controlling cholesterol biosynthesis, an unbiased forward genetics approach named validation-based insertional mutagenesis (VBIM) system was used to isolate and characterize the 25-hydroxycholesterol (25-HC)-resistant and SR-12813-resistant mutants.

Flotillins play an essential role in Niemann-Pick C1-like 1-mediated cholesterol uptake.

Dietary absorption is a major way for mammals to obtain cholesterol, which is mediated by Niemann-Pick C1-like 1 (NPC1L1) via vesicular endocytosis. One fundamental question in this process is how free cholesterol is efficiently taken up through the internalization of NPC1L1. Using exogenously expressed NPC1L1-EGFP, we show that the lipid raft proteins flotillins associate with NPC1L1 and their localization is regulated by NPC1L1 during intracellular trafficking.

The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1.

Niemann-Pick C1-like 1 (NPC1L1) is a polytopic transmembrane protein that plays a critical role in cholesterol absorption. Ezetimibe, a hypocholesterolemic drug, has been reported to bind NPC1L1 and block cholesterol absorption. However, the molecular mechanism of NPC1L1-mediated cholesterol uptake and how ezetimibe inhibits this process are poorly defined.

[Comparison of vitrification cryopreservation among different stages of mouse embryos].

The cryopreservation of different embryo stages collected from ICR, C57BL/6 and F1 of DBA*C57BL/6 was carried out by using vitrification method. The morphology, in vitro development and birth rates of these embryos were compared after frozen-thawed. The results showed that more than 75% of the morphology from 2-cell embryos to morula stages from different strains was normal, the normal morphology rates of 8-cell embryos being the highest, while those of blastulas being the lowest.