The lipolysis-stimulated lipoprotein receptor, LSR, is a multimeric protein complex in the liver that undergoes conformational changes upon binding of free fatty acids, thereby revealing a binding site(s) that recognizes both apoB and apoE. Complete inactivation of the LSR gene is embryonic lethal in mice. Here we show that removal of a single LSR allele (LSR ؊/؉ ) caused statistically significant increases in both plasma triglyceride and cholesterol levels, a 2-fold increase in plasma triglyceride changes during the post-prandial phase, and delayed clearance of lipid emulsions or a high fat meal. The longer postprandial lipoprotein clearance time observed in LSR ؊/؉ mice was further increased in LSR ؊/؉ mice lacking functional low density lipoprotein (LDL) receptors. LSR ؊/؉ mice placed on a Westerntype diet displayed higher plasma triglycerides and cholesterol levels, increased triglyceride-rich lipoproteins and LDL, and increased aorta lipid content, as compared with control mice on the same diet. Furthermore, a direct correlation was observed between the hyperlipidemia and weight gain but only in the LSR ؊/؉ mice. Knockdown of LSR expression by small interfering RNA in mouse Hepa1-6 cells led to decreased internalization of both DiI-labeled cyclohexanedione-LDL and very low density lipoprotein in the presence of oleate. These data led us to conclude that LSR contributes to the physiological clearance of atherogenic triglyceride-rich lipoproteins and LDL. We propose that LSR cooperates with the LDL receptor in the final hepatic processing of apoB-containing lipoproteins and represents a novel therapeutic target for the treatment of hyperlipidemia associated with obesity and atherosclerosis. Triglyceride (TG)2 -rich apoB-containing lipoproteins are produced by the liver as VLDL or by the intestine as chylomicrons (1). Both types of particles deliver their TG load to peripheral tissues through interactions with lipoprotein lipase (LpL) anchored to capillary endothelium heparan sulfate proteoglycans (HSPGs) (1). The residual cholesterol enriched inter-mediate density lipoprotein (IDL) and LDL for VLDL, and chylomicrons remnants are then removed from the circulation by hepatocytes. Clearance of these lipoproteins in the liver is a complex process through which the particles enter the space of Disse, bind to HSPGs, acquire apoE, and interact with hepatic lipase and LpL (2). After this, the residual particles are delivered to endocytic receptors for cellular internalization and degradation (3).The LDL receptor (LDL-R) accounts for most of LDL removal and contributes to part of the uptake of chylomicron remnants (4, 5). This highly informative endocytic receptor prototype nevertheless leaves two unsolved issues regarding apoB-containing lipoprotein clearance. First, in the absence of functional LDL-R, the amount of LDL cleared daily is 2-fold greater than that of subjects with normal LDL-R activity (6) and has been shown to take place in the liver (7). Second, the clearance of intestinally derived chylomicron remnan...
Transglutaminase type 1 (TGase 1) is a member of a class of enzymes that catalyze the cross-linking of proteins, a characteristic feature of epidermal differentiation and squamous metaplasia. The role of TGase 1 has been extensively studied in epidermis but not in the lung. Using a polyclonal anti-TGase 1 antibody prepared in our laboratory (TGase-lac), TGase 1 expression in normal bronchial epithelium, bronchial preinvasive lesions, and lung cancer was characterized. The specificity of the antibody was confirmed by the presence in squamous differentiated bronchial cells of specific 106-kD and 92-kD bands by Western blotting. In addition, immunohistochemistry displayed a recognized pattern of labeling in both normal and tumor cells beneath the cytoplasmic membrane and within the cytosol. TGase 1 was shown to be expressed by cells from bronchial epithelium and bronchial preinvasive lesions, strongly expressed in most non-small-cell lung cancer tumor cells and in apoptotic bodies, but weakly expressed in small-cell lung cancer. The distribution of TGase 1 mRNA correlated with the immunohistochemical profile. These observations suggest that TGase 1 expression is a normal feature of bronchial epithelium and is linked to the process of squamous differentiation occurring in preinvasive lesions. Its role in lung cancer remains to be clarified.
Some commercial hydrolysed diets contain carbohydrate proteins. Some dogs have circulating IgE antibodies targeting these proteins. The clinical significance of these findings is unknown.
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