Dietary cholesterol consumption and intestinal cholesterol absorption contribute to plasma cholesterol levels, a risk factor for coronary heart disease. The molecular mechanism of sterol uptake from the lumen of the small intestine is poorly defined. We show that Niemann-Pick C1 Like 1(NPC1L1) protein plays a critical role in the absorption of intestinal cholesterol. NPC1L1 expression is enriched in the small intestine and is in the brush border membrane of enterocytes. Although otherwise phenotypically normal, NPC1L1-deficient mice exhibit a substantial reduction in absorbed cholesterol, which is unaffected by dietary supplementation of bile acids. Ezetimibe, a drug that inhibits cholesterol absorption, had no effect in NPC1L1 knockout mice, suggesting that NPC1L1 resides in an ezetimibe-sensitive pathway responsible for intestinal cholesterol absorption.

Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are metabolites formed by gut microbiota from complex dietary carbohydrates. Butyrate and acetate were reported to protect against diet-induced obesity without causing hypophagia, while propionate was shown to reduce food intake. However, the underlying mechanisms for these effects are unclear. It was suggested that SCFAs may regulate gut hormones via their endogenous receptors Free fatty acid receptors 2 (FFAR2) and 3 (FFAR3), but direct evidence is lacking. We examined the effects of SCFA administration in mice, and show that butyrate, propionate, and acetate all protected against diet-induced obesity and insulin resistance. Butyrate and propionate, but not acetate, induce gut hormones and reduce food intake. As FFAR3 is the common receptor activated by butyrate and propionate, we examined these effects in FFAR3-deficient mice. The effects of butyrate and propionate on body weight and food intake are independent of FFAR3. In addition, FFAR3 plays a minor role in butyrate stimulation of Glucagon-like peptide-1, and is not required for butyrate- and propionate-dependent induction of Glucose-dependent insulinotropic peptide. Finally, FFAR3-deficient mice show normal body weight and glucose homeostasis. Stimulation of gut hormones and food intake inhibition by butyrate and propionate may represent a novel mechanism by which gut microbiota regulates host metabolism. These effects are largely intact in FFAR3-deficient mice, indicating additional mediators are required for these beneficial effects.

Niemann-Pick C1 Like 1 (NPC1L1) is a protein localized in jejunal enterocytes that is critical for intestinal cholesterol absorption. The uptake of intestinal phytosterols and cholesterol into absorptive enterocytes in the intestine is not fully defined on a molecular level, and the role of NPC1L1 in maintaining whole body cholesterol homeostasis is not known. NPC1L1 null mice had substantially reduced intestinal uptake of cholesterol and sitosterol, with dramatically reduced plasma phytosterol levels. The NPC1L1 null mice were completely resistant to diet-induced hypercholesterolemia, with plasma lipoprotein and hepatic cholesterol profiles similar to those of wild type mice treated with the cholesterol absorption inhibitor ezetimibe. Cholesterol/cholate feeding resulted in down-regulation of intestinal NPC1L1 mRNA expression in wild type mice. NPC1L1 deficiency resulted in up-regulation of intestinal hydroxymethylglutaryl-CoA synthase mRNA and an increase in intestinal cholesterol synthesis, down-regulation of ABCA1 mRNA, and no change in ABCG5 and ABCG8 mRNA expression. NPC1L1 is required for intestinal uptake of both cholesterol and phytosterols and plays a major role in cholesterol homeostasis. Thus, NPC1L1 may be a useful drug target for the treatment of hypercholesterolemia and sitosterolemia.Cholesterol absorption of both dietary cholesterol and cholesterol cleared from the liver through biliary secretion contributes along with regulation of cholesterol biosynthesis to maintain a tight control of cholesterol homeostasis. The mechanism by which cholesterol moves from the intestinal lumen into the absorptive enterocytes lining the proximal small intestine is poorly understood. The identification of ezetimibe as a potent selective inhibitor of intestinal cholesterol uptake and absorption confirmed this mechanism as a key point of therapeutic intervention for lowering plasma cholesterol levels and indicated that this process is mediated by a specific transporter (1-4). Based on the properties of ezetimibe in animal models of cholesterol uptake, it was predicted that such a transporter would be expressed in jejunal enterocytes and localized to the brush border membrane, which forms the interface between the intestinal lumen and the intracellular compartments responsible for cholesterol esterification and packaging into chylomicrons.Through studies designed to understand the mechanism by which ezetimibe inhibits cholesterol absorption, we recently identified Niemann-Pick C1 Like 1 (NPC1L1) 1 as a critical protein for the intestinal absorption of dietary and biliary cholesterol (5). NPC1L1 was identified through a genomics-bioinformatics approach by sequencing an expression sequence tags library from rat jejunum, annotating the sequences, and searching databases for intestinal proteins with features of a cholesterol transporter (5). NPC1L1 was found to be highly expressed in the jejunum and localized on the surface of the absorptive enterocytes. Mice deficient in NPC1L1 exhibited a significant reduction in chol...

The development of advanced catalysts for efficient electrochemical energy conversion technologies to alleviate the reliance on fossil fuels has attracted considerable interest in the last decades. Insight into the roles of reactive sites in nanomaterials is significant for understanding and implementing the design principles of nanocatalysts. Recently, the essential role of defects, including vacancies, reconstructed defects, and doped non-metal (or metal)-defect-based motifs, have been widely demonstrated to promote the diverse electrochemical processes (e.g., O 2 [or CO 2 ] reduction reactions and H 2 [or O 2 ] evolution reactions). Nevertheless, the in-depth exploration of the underlying defect electrocatalytic mechanism is still in its infancy. This review summarizes the state-ofthe-art defect engineering strategies for designing highly efficient electrochemical nanocatalysts with special emphasis on the correlation between defect structures and electrocatalytic properties. Finally, some perspectives on the challenges and future research directions in this promising area are presented.

Controllably constructing nitrogen‐modified divacancies (ND) in carbon substrates to immobilize atomic Fe species and unveiling the advantageous configuration is still challenging, but indispensable for attaining optimal Fe−N−C catalysts for the oxygen reduction reaction (ORR). Herein, a fundamental investigation of unfolding intrinsically superior edge‐ND trapped atomic Fe motifs (e‐ND−Fe) relative to an intact center model (c‐ND−Fe) in ORR electrocatalysis is reported. Density functional theory calculations reveal that local electronic redistribution and bandgap shrinkage for e‐ND−Fe endow it with a lower free‐energy barrier toward direct four‐electron ORR. Inspired by this, a series of atomic Fe catalysts with adjustable ND−Fe coordination are synthesized, which verify that ORR performance highly depends on the concentration of e‐ND−Fe species. Remarkably, the best e‐ND−Fe catalyst delivers a favorable kinetic current density and halfwave potential that can be comparable to benchmark Pt−C under acidic conditions. This work will guide to develop highly active atomic metal catalysts through rational defect engineering.

Defective or heteroatom-doped metal-free carbon materials (MFCMs) have been regarded as efficient oxygen reduction reaction (ORR) catalysts in the past decade. However, the active centers for ORR in MFCMs are hard to confirm precisely and synthesize controllably through common methods such as high-temperature pyrolysis or heteroatom doping. To verify the precise structure acting as the active center for the ORR, we first report two crystalline metal-free thiophene-sulfur covalent organic frameworks (MFTS-COFs) as ORR catalysts. The MFTS-COFs show more positive catalytic capability than the thiophenefree COF, indicating that pentacyclic thiophene-sulfur building blocks act as active centers to induce ORR catalytic activity. MFTS-COFs with higher contents of thiophene-sulfur exhibit better ORR performance. The experimental identification is supported by density functional theory calculations. These results thus demonstrate that rational design and precise synthesis of metal-free crystalline organic materials can promote the development of new ORR catalysts.

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Zinc–air batteries (ZABs) have attracted extensive attention due to their remarkable high theoretical energy output. They represent one of the most promising future power sources. However, many barriers restrict their application on a large scale. One of the main challenges is the sluggish rates of the oxygen‐reduction reaction (ORR) and oxygen‐evolution reaction (OER), which govern the discharging and charging processes of the battery, respectively. Here, recent advances related to oxygen electrocatalyst materials for ZABs are discussed. Detailed discussions will focus on unifunctional ORR electrocatalysts and bifunctional ORR and OER electrocatalysts. Pt‐based nanomaterials, as the best ORR electrocatalysts, possess the virtue of high activity, but have the disadvantages of high cost, scarcity, and poor stability. Thus, materials based on transition metals (alloys, metal oxides, metal nitrides, and spinel oxides) and metal‐free materials are widely investigated as nonprecious ORR catalysts owing to their promising catalytic activities. As for bifunctional ORR and OER electrocatalysts, the following two categories are introduced: (i) metal‐based materials, including single metal/metal‐oxides‐based materials and mixed‐metal/metal‐oxides‐based materials; and (ii) metal‐free materials. Finally, perspectives on the continuous research and limitation of the current ZAB technology are provided.