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Biomedical subjects

M S Brown

Publications and source records attributed to M S Brown.

At least 37 records · Page 2Linked to original sources
PubMed2001

Strabismus due to flap tear of a rectus muscle.

PURPOSE: To present a previously unreported avulsion-type injury of the rectus muscle, usually the inferior rectus, and detail its diagnosis and operative repair. METHODS: Thirty-five patients underwent repair of flap tears of 42 rectus muscles. The muscle abnormality was often subtle, with narrowing or thinning of the remaining attached global layer of muscle. The detached flap of external (orbital) muscle was found embedded in surrounding orbital fat and connective tissue. Retrieval and repair were performed in each case. RESULTS: Fourteen patients had orbital fractures, 7 had blunt trauma with no fracture, and 9 had suspected trauma but did not undergo computed tomographic scan. Five patients experienced this phenomenon following retinal detachment repair. Diagnostically, the predominant motility defect in 25 muscles was limitation toward the field of action of the muscle, presumably as a result of a tether created by the torn flap. These tethers simulated muscle palsy. Seventeen muscles were restricted away from their field of action, simulating entrapment. The direction taken by the flap during healing determined the resultant strabismus pattern. All patients presenting with gaze limitation toward an orbital fracture had flap tears. The worst results following flap tear repair were seen in patients who had undergone orbital fracture repair before presentation, patients who had undergone previous attempts at strabismus repair, and patients who experienced the longest intervals between the precipitating event and the repair. The best results were obtained in patients who underwent simultaneous fracture and strabismus repair or early strabismus repair alone. CONCLUSIONS: Avulsion-type flap tears of the extraocular muscles are a common cause of strabismus after trauma, and after repair for retinal detachment. Early repair produces the best results, but improvement is possible despite long delay.

Adolescent↗
PubMed2000

Unsaturated fatty acids down-regulate srebp isoforms 1a and 1c by two mechanisms in HEK-293 cells.

Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that increase the synthesis of fatty acids as well as cholesterol in animal cells. All three SREBP isoforms (SREBP-1a, -1c, and -2) are subject to feedback regulation by cholesterol, which blocks their proteolytic release from membranes. Previous data indicate that the SREBPs are also negatively regulated by unsaturated fatty acids, but the mechanism is uncertain. In the current experiments, unsaturated fatty acids decreased the nuclear content of SREBP-1, but not SREBP-2, in cultured human embryonic kidney (HEK)-293 cells. The potency of unsaturated fatty acids increased with increasing chain length and degree of unsaturation. Oleate, linoleate, and arachidonate were all effective, but the saturated fatty acids palmitate and stearate were not effective. Down-regulation occurred at two levels. The mRNAs encoding SREBP-1a and SREBP-1c were markedly reduced, and the proteolytic processing of these SREBPs was inhibited. When SREBP-1a was produced by a cDNA expressed from an independent promoter, unsaturated fatty acids reduced nuclear SREBP-1a without affecting the mRNA level. There was no effect when the cDNA encoded a truncated version that was not membrane-bound. When administered together, sterols and unsaturated fatty acids potentiated each other in reducing nuclear SREBP-1. In the absence of fatty acids, sterols did not cause a sustained reduction of nuclear SREBP-1, but they did reduce nuclear SREBP-2. We conclude that unsaturated fatty acids, as well as sterols, can down-regulate nuclear SREBPs and that unsaturated fatty acids have their greatest inhibitory effects on SREBP-1a and SREBP-1c, whereas sterols have their greatest inhibitory effects on SREBP-2.

Base Sequence↗
PubMed2000

Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta.

The liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily that are bound and activated by oxysterols. These receptors serve as sterol sensors to regulate the transcription of gene products that control intracellular cholesterol homeostasis through catabolism and transport. In this report, we describe a novel LXR target, the sterol regulatory element-binding protein-1c gene (SREBP-1c), which encodes a membrane-bound transcription factor of the basic helix-loop-helix-leucine zipper family. SREBP-1c expression was markedly increased in mouse tissues in an LXR-dependent manner by dietary cholesterol and synthetic agonists for both LXR and its heterodimer partner, the retinoid X receptor (RXR). Expression of the related gene products, SREBP-1a and SREBP-2, were not increased. Analysis of the mouse SREBP-1c gene promoter revealed an RXR/LXR DNA-binding site that is essential for this regulation. The transcriptional increase in SREBP-1c mRNA by RXR/LXR was accompanied by a similar increase in the level of the nuclear, active form of the SREBP-1c protein and an increase in fatty acid synthesis. Because this active form of SREBP-1c controls the transcription of genes involved in fatty acid biosynthesis, our results reveal a unique regulatory interplay between cholesterol and fatty acid metabolism.

Animals↗
PubMed2000

Overexpression of membrane domain of SCAP prevents sterols from inhibiting SCAP.SREBP exit from endoplasmic reticulum.

SCAP (SREBP cleavage-activating protein) forms a complex with sterol regulatory element-binding proteins (SREBPs) and escorts them from the endoplasmic reticulum (ER) to the Golgi complex where proteases release transcriptionally active segments of SREBPs, which enter the nucleus to activate lipid synthesis. The NH(2)-terminal segment of SCAP contains eight transmembrane helices, five of which (TM2-6) comprise the sterol-sensing domain. This domain responds to sterols by causing the SCAP.SREBP complex to be retained in the ER, preventing proteolytic release and reducing transcription of lipogenic genes. Here, we use transfection techniques to overexpress a segment of SCAP containing transmembrane helices 1-6 in hamster and human cells. This segment does not interfere with SCAP.SREBP movement to the Golgi in the absence of sterols, but it prevents sterols from suppressing this movement. This block is abolished when SCAP(TM1-6) contains a point mutation (Y298C) that is known to abolish the activity of the sterol-sensing domain. We interpret these findings to indicate that sterols cause the SCAP.SREBP complex to bind to an ER retention protein through an interaction that involves the sterol-sensing domain. The SCAP(TM1-6) segment competes with the SCAP.SREBP complex for binding to this putative retention protein, thereby liberating the SCAP.SREBP complex so that it can move to the Golgi despite the presence of sterols. These studies provide a potential mechanistic explanation for the ability of sterols to block SCAP.SREBP movement from the ER and thereby to control lipid synthesis in animal cells.

Animals↗
PubMed2000

Molecular characterization of human acetyl-CoA synthetase, an enzyme regulated by sterol regulatory element-binding proteins.

Through suppressive subtractive hybridization, we identified a new gene whose transcription is induced by sterol regulatory element-binding proteins (SREBPs). The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. ACS genes were isolated previously from yeast, but not from animal cells. Recombinant human ACS was produced by expressing the cloned cDNA transiently in human cells. After purification by nickel chromatography, the 701-amino acid cytosolic enzyme was shown to function as a monomer. The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. As expected for a gene controlled by SREBPs, ACS mRNA was induced when cultured cells were deprived of sterols and repressed by sterol addition. The pattern of regulation resembled the regulation of enzymes of fatty acid synthesis. ACS mRNA was also elevated in livers of transgenic mice that express dominant-positive versions of all three isoforms of SREBP. We conclude that ACS mRNA, and hence the ability of cells to activate acetate, is regulated by SREBPs in parallel with fatty acid synthesis in animal cells.

Acetate-CoA Ligase↗
PubMed2000

Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes.

SREBPs exit the ER in a complex with SCAP. Together, they move to the Golgi where SREBP is cleaved, releasing a fragment that activates genes encoding lipid biosynthetic enzymes. Sterols block ER exit, preventing cleavage, decreasing transcription, and achieving feedback control of lipid synthesis. Here, we report an in vitro system to measure incorporation of SCAP into ER vesicles. When membranes were isolated from sterol-depleted cells, SCAP entered vesicles in a reaction requiring nucleoside triphosphates and cytosol. SCAP budding was diminished in membranes from sterol-treated cells. Kinetics of induction of budding in vitro matched kinetics of ER exit in living cells expressing GFP-SCAP. These data localize the sterol-regulated step to budding of SCAP from ER and provide a system for biochemical dissection.

Animals↗
PubMed2000

Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by site-2 protease.

The NH(2)-terminal domains of membrane-bound sterol regulatory element-binding proteins (SREBPs) are released into the cytosol by regulated intramembrane proteolysis, after which they enter the nucleus to activate genes encoding lipid biosynthetic enzymes. Intramembrane proteolysis is catalyzed by Site-2 protease (S2P), a hydrophobic zinc metalloprotease that cleaves SREBPs at a membrane-embedded leucine-cysteine bond. In the current study, we use domain-swapping methods to localize the residues within the SREBP-2 membrane-spanning segment that are required for cleavage by S2P. The studies reveal a requirement for an asparagine-proline sequence in the middle third of the transmembrane segment. We propose a model in which the asparagine-proline sequence serves as an NH(2)-terminal cap for a portion of the transmembrane alpha-helix of SREBP, allowing the remainder of the alpha-helix to unwind partially to expose the peptide bond for cleavage by S2P.

Amino Acid Sequence↗
PubMed2000

ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.

ATF6 is a membrane-bound transcription factor that activates genes in the endoplasmic reticulum (ER) stress response. When unfolded proteins accumulate in the ER, ATF6 is cleaved to release its cytoplasmic domain, which enters the nucleus. Here, we show that ATF6 is processed by Site-1 protease (S1P) and Site-2 protease (S2P), the enzymes that process SREBPs in response to cholesterol deprivation. ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. ATF6 processing required the RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively. Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress. ATF6 processing did not require SCAP, which is essential for SREBP processing. We conclude that S1P and S2P are required for the ER stress response as well as for lipid synthesis.

Activating Transcription Factor 6↗
PubMed2000

PCR analysis of the immunoglobulin heavy chain gene in polyclonal processes can yield pseudoclonal bands as an artifact of low B cell number.

Polymerase chain reaction (PCR)-based analysis for detecting immunoglobulin heavy chain gene (IgH) rearrangements in lymphoproliferative disorders is well established. The presence of one or two discrete bands is interpreted as a monoclonal proliferation, whereas a smear pattern represents a polyclonal population. Prompted by our observation of discrete bands in histologically reactive processes with a relative paucity of B cells, we sought to determine whether low numbers of B cells in biopsy specimens could artifactually produce pseudomonoclonal bands. We performed IgH PCR analysis on serially diluted DNA samples from 5 B cell non-Hodgkin's lymphomas (B-NHLs), 5 reactive lymph nodes, 5 reactive tonsils and 10 microdissected germinal centers from a lymph node with follicular hyperplasia. We also assessed multiple aliquots of DNA samples from small biopsy specimens of reactive lymphocytic processes from the stomach (5 cases). PCR products were evaluated using high resolution agarose or polyacrylamide gels, and DNA sequencing was performed on IgH PCR products from two reactive germinal centers, which yielded monoclonal bands of identical size. All 5 B-NHLs harboring monoclonal B cell populations yielded single discrete bands, which were maintained in all dilutions. By contrast, all of the reactive lesions with polyclonal patterns at 50 ng/microl starting template concentration showed strong pseudomonoclonal bands at dilutions of 1:1,000 to 1:1,500 in placental DNA. Two of the microdissected reactive germinal centers that showed bands of identical size on duplicate reactions were proven to have different IgH sequences by sequencing. We conclude that specimens containing low numbers of polyclonal B cells may produce pseudomonoclonal bands on IgH PCR analysis. IgH PCR analysis should be performed on multiple aliquots of each DNA sample, and only samples that yield reproducible bands of identical size can be reliably interpreted as monoclonal.

B-Lymphocytes↗
PubMed2000

Coitus, the proximate determinant of conception: inter-country variance in sub-Saharan Africa.

There is a general consensus in the literature that fertility differences between populations can be accounted for by differences in just four key proximate determinants: nuptiality, the postpartum non-susceptible period, contraception and abortion. Natural fecundibility is generally assumed to be constant between populations. This paper puts the theoretical and empirical case for a re-evaluation of that assumption, drawing on the under-utilized data on sexual activity collected in the Demographic Health Surveys (DHSs). Using data for married women in nine African countries, the analysis finds substantial population level differences in mean monthly coital frequency, which, if accurate, suggest an important demographic effect. There is a clear regional patterning to these differences, with levels of activity considerably lower among women in the West African populations included in the study than those from East and southern Africa. For West Africa in particular the data indicate the normality of exceptionally long periods of very infrequent or no intercourse by married women outside the period of postpartum abstinence. The findings challenge prevailing presumptions concerning susceptibility to pregnancy in marriage on which statistics for unmet need for family planning are derived. While doubts are raised over the precision of the sexual activity data used, the paper argues for the need for a greater effort to operationalize the 'proximate determinant of conception', not only for more accurate fertility modelling, but also as a planning tool for a more sensitive provision of family planning services in Africa.

Adolescent↗
PubMed2000

The effect of upper blepharoplasty on eyelid position when performed concomitantly with Müller muscle-conjunctival resection.

PURPOSE: To determine the effect on eyelid elevation of excising excess skin, orbicularis oculi muscle, and herniated orbital fat and reconstructing the upper eyelid crease (blepharoplasty) concomitant with a Müller muscle-conjunctival resection. METHODS: The charts of 202 patients who had undergone Müller muscle-conjunctival resection during an 8-year interval were reviewed. Three hundred forty-five eyelids were divided into two groups. Group 1 (n = 162) underwent a Müller muscle-conjunctival resection only, and group 2 (n = 183) had this procedure combined with excision of skin, orbicularis muscle, and herniated orbital fat with upper eyelid crease reconstruction. Each group was divided into three subgroups based on the amount of Müller muscle-conjunctival resection. Subgroup A had resection less than 7.75 mm; subgroup B, resection of 7.75 to 8.75 mm; and subgroup C, resection greater than 8.75 mm. The change in margin reflex distance-1 (MRD1) measurements of the upper eyelid levels (postoperative MRD1 minus preoperative MRD1) were calculated and compared between groups. RESULTS: The mean (+/- standard deviation) change in MRD1 was, respectively, 2.3 +/-1.0 mm and 1.9+/-1.0 mm for groups 1A and 2A; 3.1+/-1.3 mm and 2.1+/-1.2 mm for groups 1B and 2B; and 3.4+/-1.2 mm and 2.8+/-1.3 for groups 1C and 2C. CONCLUSIONS: Blepharoplasty performed concomitant with a Müller muscle-conjunctival resection reduced the anticipated postoperative eyelid elevation by as much as 1 mm. Surgeons who perform these procedures together should be aware that a larger Müller muscle-conjunctival resection may be required to obtain the desired increase in eyelid height postoperatively.

Blepharoplasty↗
PubMed2000

Knowledge-based segmentation of thoracic computed tomography images for assessment of split lung function.

The assessment of differential left and right lung function is important for patients under consideration for lung resection procedures such as single lung transplantation. We developed an automated, knowledge-based segmentation algorithm for purposes of deriving functional information from dynamic computed tomography (CT) image data. Median lung attenuation (HU) and area measurements were automatically calculated for each lung from thoracic CT images acquired during a forced expiratory maneuver as indicators of the amount and rate of airflow. The accuracy of these derived measures from fully automated segmentation was validated against those from segmentation using manual editing by an expert observer. A total of 1313 axial images were analyzed from 49 patients. The images were segmented using our knowledge-based system that identifies the chest wall, mediastinum, trachea, large airways and lung parenchyma on CT images. The key components of the system are an anatomical model, an inference engine and image processing routines, and segmentation involves matching objects extracted from the image to anatomical objects described in the model. The segmentation results from all images were inspected by the expert observer. Manual editing was required to correct 183 (13.94%) of the images, and the sensitivity, specificity, and accuracy of the knowledge-based segmentation were greater than 98.55% in classifying pixels as lung or nonlung. There was no significant difference between median lung attenuation or area values from automated and edited segmentations (p > 0.70). Using the knowledge-based segmentation method we can automatically derive indirect quantitative measures of single lung function that cannot be obtained using conventional pulmonary function tests.

Algorithms↗
PubMed2000

Evaluation of models of acute and subacute acidosis on dry matter intake, ruminal fermentation, blood chemistry, and endocrine profiles of beef steers.

Crossbred steers (n = 20; 316 +/- 4 kg BW), each fitted with a ruminal cannula, were used to evaluate the effects of acute acidosis (AA) and subacute acidosis (SA) on DMI, ruminal fermentation, blood chemistry, and endocrine profiles. Animals were blocked by BW and assigned to treatments including 1) intraruminal (via cannula) steam-flaked corn (3% of BW; AA); 2) intraruminal dry-rolled wheat:dry-rolled corn (50:50; 1.5% of BW; SA); 3) offering forage-adapted steers ad libitum access to a 50% concentrate diet (AA control; AC); and 4) offering 50% concentrate diet-adapted steers ad libitum access to a 50% concentrate diet (SA control; SC). Samples of ruminal fluid and whole blood were collected on the day of the challenge (d 0) and 3, 7, 10, and 14 d after the challenge. Daily DMI responded quadratically (P < 0.01) through d 7 for AA and SA steers and increased linearly (P < 0.01) for AC steers. Dry matter intake by AA steers reached a nadir (< 3 kg/d) on d 3 and gradually increased to a level similar to other treatments (7 kg/d) by d 10, whereas DMI by SA steers increased through d 3. Blood pH, bicarbonate, base excess, and total CO2 were decreased (P < 0.03) for AA steers and increased (P < 0.03) for SC steers through d 7. Ruminal pH decreased quadratically (P < 0.01) in AA and AC steers and increased (P = 0.01) in SA steers through d 7. Ruminal total lactate concentration and osmolality responded quadratically (P < 0.01) for AA and AC steers. Ruminal total lactate peaked on d 3 for AA steers and on d 0 for AC and decreased to basal concentrations by d 7. Plasma NEFA concentration increased (P < 0.04) on d 3 and 7 for AA steers. Serum Na decreased (P < 0.05) on d 0 for AA and SA steers and on d 7 and 14 for AA steers. Serum P decreased (P = 0.01) for AA steers through d 7 and decreased quadratically (P = 0.01) for AC steers through d 7. Serum albumin and cholesterol decreased (P < 0.02) for AA and AC steers through d 7. Area under the GH curve decreased (P = 0.02) for AA and AC steers through d 7. Considerable variation was evident in the ability of an animal to cope with a carbohydrate challenge. Results of data modeling generally suggest that serum amylase activity, cholesterol and potassium concentrations, and plasma NEFA concentrations were useful in distinguishing between steers classified as experiencing subacute acidosis or not affected by a carbohydrate challenge.

Acidosis↗
PubMed2000

Influence of feed intake fluctuation and frequency of feeding on nutrient digestion, digesta kinetics, and ruminal fermentation profiles in limit-fed steers.

Nine crossbred beef steers (344 +/- 26 kg) fitted with ruminal cannulas were used in a randomized complete block design to evaluate the effects of feeding frequency and feed intake fluctuation on total tract digestion, digesta kinetics, and ruminal fermentation profiles in limit-fed steers. In Period 1, steers were allotted randomly to one of four dietary treatments: 1) feed offered once daily at 0800; 2) feed offered once daily at 0800 with a 10% fluctuation in day-to-day feed intake; 3) feed offered twice daily at 0800 and 1700; and 4) feed offered twice daily at 0800 and 1700 with a 10% fluctuation in a day-to-day feed intake. In Period 2, steers were reallocated across treatments. The 90% concentrate diet was fed at 90% of the ad-libitum consumption by each steer. Chromium-EDTA and Yb-labeled steam-flaked corn were intraruminally infused at 0800 on d 1 and 3 and Co-EDTA and Er-labeled steam-flaked corn were infused on d 2 and 4 of the 4-d collection period. Ruminal samples were collected at 0, 3, 6, 9, 12, 15, 18, and 24 h after the 0800 feeding, and total feces were collected for 4 d. Total tract digestibilities of OM, N, and starch were lowest (fluctuation x frequency, P < .05) when feed was offered twice daily with a 10% fluctuation in intake. Ruminal fluid volume and passage rate were not affected (P > .10) by feeding frequency or intake fluctuation. A frequency x fluctuation x sampling time interaction occurred (P < .01) for ruminal pH. Steers fed a constant amount of feed once daily had higher (P < .05) ruminal pH at 0, 3, 18, and 24 h than steers fed once daily with a 10% fluctuation in feed intake. Total VFA concentration was greater (P < .01) at 9 h after the 0800 feeding when feed was offered once vs twice daily. Feeding twice daily increased (P < .05) the molar proportion of acetate and decreased (P < .05) the molar proportion of propionate. Increasing feeding frequency resulted in a more stable ruminal environment; however, the increased acetate:propionate ratio with twice-daily feeding might result in lower efficiency of energy utilization by limit-fed steers.

Animal Feed↗
PubMed2000

Effect of degree of corn processing on urinary nitrogen composition, serum metabolite and insulin profiles, and performance by finishing steers.

Two experiments were conducted to determine the effect of degree of corn processing on urinary ammonia and urea N concentrations, serum metabolite and insulin concentrations, and feedlot performance of steers. Corn was processed by either dry rolling to .54 kg/L bulk density (DR42; 42 lb/bushel) or steam flaking to a bulk density of .36 or .26 kg/L (28 [SF28] and 20 [SF20] lb/bushel, respectively). Degrees of processing were selected to generate final products with 25, 50, or 75% enzymatically available starch. Available starch, expressed as a percentage of total starch for DR42, SF28, and SF20, averaged 24.5, 56.4, and 81.1% in Exp. 1 and 22.4, 60.1, and 80.1% in Exp. 2. In Exp. 1, 29 steers were housed in individual outdoor pens and adapted to a 90% concentrate diet over 21 d. Whole blood and urine were collected before feeding and at 4 and 8 h after feeding on d 0, 7, 14, 21, 28, 84, and 140. Daily DMI decreased linearly (P < .03) as degree of processing increased, whereas water intake did not differ (P > .42) among treatments. Average daily gain, ADG:DMI, and hot carcass weight responded quadratically (P < .04) to an increasing degree of processing. Urinary ammonia and urea N concentrations were not influenced (P > .30) by degree of processing. Whole blood packed cell volume, serum glucose, creatinine, D(-)-lactate, L(+)-lactate, and lactate dehydrogenase activity did not differ (P > .15) among treatments. For insulin data, ME intake on the day of sample collection was evaluated as a covariate. On d 28, serum insulin (2.49, 2.95, and 1.80+/-.33 ng/mL) responded quadratically (P = .04) as degree of processing increased. Serum insulin did not differ (P = .52) on d 84, whereas insulin (5.77, 7.51, and 4.12+/-.98 ng/mL) responded quadratically (P = .02) on d 140. In Exp. 2,216 steers were blocked by BW into two blocks (18 pens; 12 steers/pen) and assigned to the same treatments used in Exp. 1. Daily DMI and carcass weight responded quadratically (P < .05), whereas ADG and ADG:DMI increased linearly (P < .04) with increasing degree of processing. Results suggest that the degree of corn processing influences serum insulin concentrations of feedlot steers; however, serum metabolites, urinary nitrogen composition, and carcass characteristics were generally not affected by degree of corn processing.

Animal Feed↗
PubMed2000

Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice.

In mice with too little fat (lipodystrophy) or too much fat (ob/ob), leptin deficiency leads to hyperglycemia, hyperinsulinemia, and insulin resistance. In both disorders, the liver overproduces glucose as a result of resistance to the normal action of insulin in repressing mRNAs for gluconeogenic enzymes. Here we show that chronic hyperinsulinemia downregulates the mRNA for IRS-2, an essential component of the insulin-signaling pathway in liver, thereby producing insulin resistance. Despite IRS-2 deficiency, insulin continues to stimulate production of SREBP-1c, a transcription factor that activates fatty acid synthesis. The combination of insulin resistance (inappropriate gluconeogenesis) and insulin sensitivity (elevated lipogenesis) establishes a vicious cycle that aggravates hyperinsulinemia and insulin resistance in lipodystrophic and ob/ob mice.

Animals↗
PubMed1999

Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi.

Cholesterol homeostasis in animal cells is achieved by regulated cleavage of membrane-bound transcription factors, designated SREBPs. Proteolytic release of the active domains of SREBPs from membranes requires a sterol-sensing protein, SCAP, which forms a complex with SREBPs. In sterol-depleted cells, SCAP escorts SREBPs from ER to Golgi, where SREBPs are cleaved by Site-1 protease (S1P). Sterols block this transport and abolish cleavage. Relocating active S1P from Golgi to ER by treating cells with brefeldin A or by fusing the ER retention signal KDEL to S1P obviates the SCAP requirement and renders cleavage insensitive to sterols. Transport-dependent proteolysis may be a common mechanism to regulate the processing of membrane proteins.

Animals↗