Breast and Cervical Cancer Screenings: A Systematic Economic Review of Patient Navigation Services.

INTRODUCTION: This paper examined the economic evidence of patient navigation services to increase breast and cervical cancer screenings among historically disadvantaged racial and ethnic populations and people with lower incomes. METHODS: The literature search strategy for this systematic review included English-language studies conducted in high-income countries that were published from database inception to December 2022. Studies on patients with existing cancer or without healthcare system involvement were excluded. Analysis was completed in January 2023. All monetary values reported are in 2022 U.S. dollars. RESULTS: The search yielded 3 breast cancer, 2 cervical cancer, and 2 multiple cancer studies that combined breast and cervical cancer with other cancer screenings. For breast cancer screening, the intervention cost per person ranged from $109 to $10,245. Two studies reported $154 and $740 as intervention cost per additional person screened. Changes in healthcare cost per person from 2 studies were $202 and $2,437. Two studies reported cost per quality-adjusted life year (QALY) gained of $3,852 and $39,159 while one study reported cost per life year (LY) gained of $22,889. For cervical cancer, 2 studies reported intervention cost per person ($103 and $794) and per additional person screened ($56 and $533) with one study reporting a cost per QALY gained ($924). DISCUSSION: All estimates of cost per QALY/LY saved for breast cancer screening were below a conservative threshold of $50,000 indicating that patient navigation services for breast cancer screening were cost-effective. There is limited evidence to determine cost-effectiveness of patient navigation services for cervical cancer screening.

Functionality of arbuscular mycorrhizal fungi varies across different growth stages of maize under drought conditions.

Physio-biochemical regulations governing crop growth period are pivotal for drought adaptation. Yet, the extent to which functionality of arbuscular mycorrhizal fungi (AM fungi) varies across different stages of maize growth under drought conditions remains uncertain. Therefore, periodic functionality of two different AM fungi i.e., Rhizophagus irregularis SUN16 and Glomus monosporum WUM11 were assessed at jointing, silking, and pre-harvest stages of maize subjected to different soil moisture gradients i.e., well-watered (80% SMC (soil moisture contents)), moderate drought (60% SMC), and severe drought (40% SMC). The study found that AM fungi significantly (p < 0.05) affected various morpho-physiological and biochemical parameters at different growth stages of maize under drought. As the plants matured, AM fungi enhanced root colonization, glomalin contents, and microbial biomass, leading to increased nutrient uptake and antioxidant activity. This boosted AM fungal activity ultimately improved photosynthetic efficiency, evident in increased photosynthetic pigments and photosynthesis. Notably, R. irregularis and G. monosporum improved water use efficiency and mycorrhizal dependency at critical growth stages like silking and pre-harvest, indicating their potential for drought resilience to stabilize yield. The principal component analysis highlighted distinct plant responses to drought across growth stages and AM fungi, emphasizing the importance of early-stage sensitivity. These findings underscore the potential of incorporating AM fungi into agricultural management practices to enhance physiological and biochemical responses, ultimately improving drought tolerance and yield in dryland maize cultivation.

A Community Guide Systematic Review: Digital HIV Pre-Exposure Prophylaxis Interventions.

INTRODUCTION: HIV preexposure prophylaxis (PrEP) is highly effective when taken as prescribed. Digital health adherence interventions have been identified as effective for improving antiretroviral therapy adherence among people with HIV, but limited evidence exists for PrEP adherence interventions among people without HIV. The purpose of this Community Guide systematic review was to present the characteristics and effectiveness of digital PrEP adherence interventions. METHODS: The author searched the CDC HIV Prevention Research Synthesis cumulative database for digital health interventions with PrEP adherence outcomes published in peer-reviewed journals from 2000 to 2022. Studies with comparison arms or pre-post data evaluating interventions in high-income countries were included. Two reviewers independently screened citations, extracted data, conducted risk of bias assessment, and resolved discrepancies through discussion. Summary effect estimates were calculated using median and interquartile interval. RESULTS: Nine studies were included and all focused on gay, bisexual, and other men who have sex with men. Eight studies were U.S.-based while the other was conducted in the Netherlands. Five were randomized control trials and four were pre-/post studies. All studies showed improved adherence in the intervention arms compared with comparison groups or preintervention data. One study also reported improvement in PrEP care retention. DISCUSSION: Digital health adherence interventions with different strategies to improve PrEP and HIV-related outcomes were identified. The small number of studies identified is a limitation. Findings from this review served as the basis for the Community Preventive Services Task Force recommendation to use these interventions to increase PrEP adherence to prevent HIV infection.

Community Health Workers to Increase Cancer Screening: 3 Community Guide Systematic Reviews.

INTRODUCTION: Many in the U.S. are not up to date with cancer screening. This systematic review examined the effectiveness of interventions engaging community health workers to increase breast, cervical, and colorectal cancer screening. METHODS: Authors identified relevant publications from previous Community Guide systematic reviews of interventions to increase cancer screening (1966 through 2013) and from an update search (January 2014-November 2021). Studies written in English and published in peer-reviewed journals were included if they assessed interventions implemented in high-income countries; reported screening for breast, cervical, or colorectal cancer; and engaged community health workers to implement part or all of the interventions. Community health workers needed to come from or have close knowledge of the intervention community. RESULTS: The review included 76 studies. Interventions engaging community health workers increased screening use for breast (median increase=11.5 percentage points, interquartile interval=5.5‒23.5), cervical (median increase=12.8 percentage points, interquartile interval=6.4‒21.0), and colorectal cancers (median increase=10.5 percentage points, interquartile interval=4.5‒17.5). Interventions were effective whether community health workers worked alone or as part of a team. Interventions increased cancer screening independent of race or ethnicity, income, or insurance status. DISCUSSION: Interventions engaging community health workers are recommended by the Community Preventive Services Task Force to increase cancer screening. These interventions are typically implemented in communities where people are underserved to improve health and can enhance health equity. Further training and financial support for community health workers should be considered to increase cancer screening uptake.

Tenant-Based Housing Voucher Programs: A Community Guide Systematic Review.

CONTEXT: Unaffordable or insecure housing is associated with poor health in children and adults. Tenant-based housing voucher programs (voucher programs) limit rent to 30% or less of household income to help households with low income obtain safe and affordable housing. OBJECTIVE: To determine the effectiveness of voucher programs in improving housing, health, and other health-related outcomes for households with low income. DESIGN: Community Guide systematic review methods were used to assess intervention effectiveness and threats to validity. An updated systematic search based on a previous Community Guide review was conducted for literature published from 1999 to July 2019 using electronic databases. Reference lists of included studies were also searched. ELIGIBILITY CRITERIA: Studies were included if they assessed voucher programs in the United States, had concurrent comparison populations, assessed outcomes of interest, were written in English, and published in peer-reviewed journals or government reports. MAIN OUTCOME MEASURES: Housing quality and stability, neighborhood opportunity (safety and poverty), education, income, employment, physical and mental health, health care use, and risky health behavior. RESULTS: Seven studies met inclusion criteria. Compared with low-income households not offered vouchers, voucher-using households reported increased housing quality (7.9 percentage points [pct pts]), decreased housing insecurity or homelessness (-22.4 pct pts), and decreased neighborhood poverty (-5.2 pct pts).Adults in voucher-using households had improved health care access and physical and mental health. Female youth experienced better physical and mental health but not male youth. Children who entered the voucher programs under 13 years of age had improved educational attainment, employment, and income in their adulthood; children's gains in these outcomes were inversely related to their age at program entry. CONCLUSION: Voucher programs improved health and several health-related outcomes for voucher-using households, particularly young children. Research is still needed to better understand household's experiences and contextual factors that influence achievement of desired outcomes.

Permanent Supportive Housing With Housing First: Findings From a Community Guide Systematic Economic Review.

INTRODUCTION: The annual economic burden of chronic homelessness in the U.S. is estimated to be as high as $3.4 billion. The Permanent Supportive Housing with Housing First (Housing First) program, implemented to address the problem, has been shown to be effective. This paper examines the economic cost and benefit of Housing First Programs. METHODS: The search of peer-reviewed and gray literature from inception of databases through November 2019 yielded 20 evaluation studies of Housing First Programs, 17 from the U.S. and 3 from Canada. All analyses were conducted from March 2019 through July 2020. Monetary values are reported in 2019 U.S. dollars. RESULTS: Evidence from studies conducted in the U.S. was separated from those conducted in Canada. The median intervention cost per person per year for U.S. studies was $16,479, and for all studies, including those from Canada, it was $16,336. The median total benefit for the U.S. studies was $18,247 per person per year, and it was $17,751 for all studies, including those from Canada. The benefit-to-cost ratio for U.S. studies was 1.80:1, and for all studies, including those from Canada, it was 1.06:1. DISCUSSION: The evidence from this review shows that economic benefits exceed the cost of Housing First Programs in the U.S. There were too few studies to determine cost-benefit in the Canadian context.

Engaging Community Health Workers to Increase Cancer Screening: A Community Guide Systematic Economic Review.

CONTEXT: The Community Preventive Services Task Force recommends engaging community health workers to increase breast, cervical, and colorectal cancer screenings on the basis of strong evidence of effectiveness. This systematic review examines the economic evidence of these interventions. EVIDENCE ACQUISITION: A systematic literature search was performed with a search period through April 2019 to identify relevant economic evaluation studies. All monetary values were adjusted to 2018 U.S. dollars, and the analysis was completed in 2019. EVIDENCE SYNTHESIS: A total of 19 studies were included in the final analysis with 3 on breast cancer, 5 on cervical cancer, 9 on colorectal cancer, and 2 that combined costs for breast and cervical cancers and for breast, cervical, and colorectal cancers. For cervical cancer screening, 2 U.S. studies reported incremental cost per quality-adjusted life year saved of $762 and $34,405. For colorectal cancer screening, 2 U.S. studies reported both a negative incremental cost and an increase in quality-adjusted life years saved with colonoscopy screening. CONCLUSIONS: Engaging community health workers to increase cervical and colorectal cancer screenings is cost effective on the basis of estimated incremental cost-effectiveness ratios that were less than the conservative $50,000 per quality-adjusted life year threshold. In addition, quality-adjusted life years saved from colorectal screening with colonoscopy were associated with net healthcare cost savings.

Permanent Supportive Housing With Housing First to Reduce Homelessness and Promote Health Among Homeless Populations With Disability: A Community Guide Systematic Review.

CONTEXT: Poor physical and mental health and substance use disorder can be causes and consequences of homelessness. Approximately 2.1 million persons per year in the United States experience homelessness. People experiencing homelessness have high rates of emergency department use, hospitalization, substance use treatment, social services use, arrest, and incarceration. OBJECTIVES: A standard approach to treating homeless persons with a disability is called Treatment First, requiring clients be "housing ready"-that is, in psychiatric treatment and substance-free-before and while receiving permanent housing. A more recent approach, Housing First, provides permanent housing and health, mental health, and other supportive services without requiring clients to be housing ready. To determine the relative effectiveness of these approaches, this systematic review compared the effects of both approaches on housing stability, health outcomes, and health care utilization among persons with disabilities experiencing homelessness. DESIGN: A systematic search (database inception to February 2018) was conducted using 8 databases with terms such as "housing first," "treatment first," and "supportive housing." Reference lists of included studies were also searched. Study design and threats to validity were assessed using Community Guide methods. Medians were calculated when appropriate. ELIGIBILITY CRITERIA: Studies were included if they assessed Housing First programs in high-income nations, had concurrent comparison populations, assessed outcomes of interest, and were written in English and published in peer-reviewed journals or government reports. MAIN OUTCOME MEASURES: Housing stability, physical and mental health outcomes, and health care utilization. RESULTS: Twenty-six studies in the United States and Canada met inclusion criteria. Compared with Treatment First, Housing First programs decreased homelessness by 88% and improved housing stability by 41%. For clients living with HIV infection, Housing First programs reduced homelessness by 37%, viral load by 22%, depression by 13%, emergency departments use by 41%, hospitalization by 36%, and mortality by 37%. CONCLUSIONS: Housing First programs improved housing stability and reduced homelessness more effectively than Treatment First programs. In addition, Housing First programs showed health benefits and reduced health services use. Health care systems that serve homeless patients may promote their health and well-being by linking them with effective housing services.

Economics of Multicomponent Interventions to Increase Breast, Cervical, and Colorectal Cancer Screening: A Community Guide Systematic Review.

CONTEXT: The Community Preventive Services Task Force recently recommended multicomponent interventions to increase breast, cervical, and colorectal cancer screening based on strong evidence of effectiveness. This systematic review examines the economic evidence to guide decisions on the implementation of these interventions. EVIDENCE ACQUISITION: A systematic literature search for economic evidence was performed from January 2004 to January 2018. All monetary values were reported in 2016 US dollars, and the analysis was completed in 2018. EVIDENCE SYNTHESIS: Fifty-three studies were included in the body of evidence from a literature search yield of 8,568 total articles. For multicomponent interventions to increase breast cancer screening, the median intervention cost per participant was $26.69 (interquartile interval [IQI]=$3.25, $113.72), and the median incremental cost per additional woman screened was $147.64 (IQI=$32.92, $924.98). For cervical cancer screening, the median costs per participant and per additional woman screened were $159.80 (IQI=$117.62, $214.73) and $159.49 (IQI=$64.74, $331.46), respectively. Two studies reported incremental cost per quality-adjusted life year gained of $748 and $33,433. For colorectal cancer screening, the median costs per participant and per additional person screened were $36.63 (IQI=$7.70, $139.23) and $582.44 (IQI=$91.10, $1,452.12), respectively. Two studies indicated a decline in incremental cost per quality-adjusted life year gained of $1,651 and $3,817. CONCLUSIONS: Multicomponent interventions to increase cervical and colorectal cancer screening were cost effective based on a very conservative threshold. Additionally, multicomponent interventions for colorectal cancer screening demonstrated net cost savings. Cost effectiveness for multicomponent interventions to increase breast cancer screening could not be determined owing to the lack of studies reporting incremental cost per quality-adjusted life year gained. Future studies estimating this outcome could assist implementers with decision making.

Team-Based Care to Improve Diabetes Management: A Community Guide Meta-analysis.

CONTEXT: Team-based care has been increasingly used to deliver care for patients with chronic conditions, but its effectiveness for managing diabetes has not been systematically assessed. EVIDENCE ACQUISITION: RCTs were identified from two sources: a high-quality, broader review comparing 11 quality improvement strategies for diabetes management (database inception to July 2010), and an updated search using the same search strategy (July 2010-October 2015). EVIDENCE SYNTHESIS: Thirty-five studies were included in the current review; a majority focused on patients with Type 2 diabetes. Teams included patients, their primary care providers, and one or two additional healthcare professionals (most often nurses or pharmacists). Random effect meta-analysis showed that, compared with controls, team-based care was associated with greater reductions in blood glucose levels (-0.5% in HbA1c, 95% CI= -0.7, -0.3) and greater improvements in blood pressure and lipid levels. Interventions also increased the proportion of patients who reached target blood glucose, blood pressure, and lipid levels, based on American Diabetes Association guidelines available at the time. Data analysis was completed in 2016. CONCLUSIONS: For patients with Type 2 diabetes, team-based care improves blood glucose, blood pressure, and lipid levels.

Expanded In-School Instructional Time and the Advancement of Health Equity: A Community Guide Systematic Review.

Expanded in-school instructional time (EISIT) may reduce racial/ethnic educational achievement gaps, leading to improved employment, and decreased social and health risks. When targeted to low-income and racial/ethnic minority populations, EISIT may thus promote health equity. Community Guide systematic review methods were used to search for qualified studies (through February 2015, 11 included studies) and summarize evidence of the effectiveness of EISIT on educational outcomes. Compared with schools with no time change, schools with expanded days improved students' test scores by a median of 0.05 standard deviation units (range, 0.0-0.25). Two studies found that schools with expanded day and year improved students' standardized test scores (0.04 and 0.15 standard deviation units). Remaining studies were inconclusive. Given the small effect sizes and a lack of information about the use of added time, there is insufficient evidence to determine the effectiveness of EISIT on academic achievement and thus health equity.

Examining the Effectiveness of Year-Round School Calendars on Improving Educational Attainment Outcomes Within the Context of Advancement of Health Equity: A Community Guide Systematic Review.

Students may lose knowledge and skills achieved in the school year during the summer break, with losses greatest for students from low-income families. Community Guide systematic review methods were used to summarize evaluations (published 1965-2015) of the effectiveness of year-round school calendars (YRSCs) on academic achievement, a determinant of long-term health. In single-track YRSCs, all students participate in the same school calendar; summer breaks are replaced by short "intersessions" distributed evenly throughout the year. In multi-track YRSCs, cohorts of students follow separate calendar tracks, with breaks at different times throughout the year. An earlier systematic review reported modest gains with single-track calendars and no gains with multi-track calendars. Three studies reported positive and negative effects for single-track programs and potential harm with multi-track programs when low-income students were assigned poorly resourced tracks. Lack of clarity about the role of intersessions as simple school breaks or as additional schooling opportunities in YRSCs leaves the evidence on single-track programs insufficient. Evidence on multi-track YRSCs is also insufficient.

Universal Motorcycle Helmet Laws to Reduce Injuries: A Community Guide Systematic Review.

CONTEXT: Motorcycle crashes account for a disproportionate number of motor vehicle deaths and injuries in the U.S. Motorcycle helmet use can lead to an estimated 42% reduction in risk for fatal injuries and a 69% reduction in risk for head injuries. However, helmet use in the U.S. has been declining and was at 60% in 2013. The current review examines the effectiveness of motorcycle helmet laws in increasing helmet use and reducing motorcycle-related deaths and injuries. EVIDENCE ACQUISITION: Databases relevant to health or transportation were searched from database inception to August 2012. Reference lists of reviews, reports, and gray literature were also searched. Analysis of the data was completed in 2014. EVIDENCE SYNTHESIS: A total of 60 U.S. studies qualified for inclusion in the review. Implementing universal helmet laws increased helmet use (median, 47 percentage points); reduced total deaths (median, -32%) and deaths per registered motorcycle (median, -29%); and reduced total injuries (median, -32%) and injuries per registered motorcycle (median, -24%). Repealing universal helmet laws decreased helmet use (median, -39 percentage points); increased total deaths (median, 42%) and deaths per registered motorcycle (median, 24%); and increased total injuries (median, 41%) and injuries per registered motorcycle (median, 8%). CONCLUSIONS: Universal helmet laws are effective in increasing motorcycle helmet use and reducing deaths and injuries. These laws are effective for motorcyclists of all ages, including younger operators and passengers who would have already been covered by partial helmet laws. Repealing universal helmet laws decreased helmet use and increased deaths and injuries.

School-Based Health Centers to Advance Health Equity: A Community Guide Systematic Review.

CONTEXT: Children from low-income and racial or ethnic minority populations in the U.S. are less likely to have a conventional source of medical care and more likely to develop chronic health problems than are more-affluent and non-Hispanic white children. They are more often chronically stressed, tired, and hungry, and more likely to have impaired vision and hearing-obstacles to lifetime educational achievement and predictors of adult morbidity and premature mortality. If school-based health centers (SBHCs) can overcome educational obstacles and increase receipt of needed medical services in disadvantaged populations, they can advance health equity. EVIDENCE ACQUISITION: A systematic literature search was conducted for papers published through July 2014. Using Community Guide systematic review methods, reviewers identified, abstracted, and summarized available evidence of the effectiveness of SBHCs on educational and health-related outcomes. Analyses were conducted in 2014-2015. EVIDENCE SYNTHESIS: Most of the 46 studies included in the review evaluated onsite clinics serving urban, low-income, and racial or ethnic minority high school students. The presence and use of SBHCs were associated with improved educational (i.e., grade point average, grade promotion, suspension, and non-completion rates) and health-related outcomes (i.e., vaccination and other preventive services, asthma morbidity, emergency department use and hospital admissions, contraceptive use among females, prenatal care, birth weight, illegal substance use, and alcohol consumption). More services and more hours of availability were associated with greater reductions in emergency department overuse. CONCLUSIONS: Because SBHCs improve educational and health-related outcomes in disadvantaged students, they can be effective in advancing health equity.

Higher Bioavailability of Organic Bound Zinc from High Zinc-Enriched Fungi.

The organic forms of trace elements are considered more bioavailable than the inorganic forms. Although yeast can enrich metal elements and convert inorganic zinc to organic species, its tolerability and transforming capacity are limited. It would therefore be very interesting to look for higher conversion and accumulation in zinc fungi to obtain organic bound zinc from the natural environment. In this paper, potato dextrose agar (PDA) medium containing 800 µg/mL zinc was used for initial screening, with twenty-two fungal strains that tolerated high zinc isolated from the natural environment, and one strain (No.LZ-1108) growing well at a zinc (II) concentration of 10,000 µg/mL. According to morphological analysis, 18S rDNA sequence analysis, and biophysical and biochemical characteristics, No.LZ-1108 was tentatively identified as Fusarium oxysporum. Using atomic absorption spectrometry, the zinc content in the No.LZ-1108 cells was found to be 6.7 mg/g dry cell. After oral administration to rats at a dose of 10 mg Zn (II)/kg body weight, the area under the plasma concentration-time curve (AUC) and the maximum zinc blood concentration (Cmax) of No.LZ-1108 and zinc gluconate were 8.10 g/L.min and 4.28 g/L.min, 23.72 µg/mL and 6.23 µg/mL, respectively. The AUC of No.LZ-1108 was significantly higher than those of zinc gluconate (P<0.05), and the mean relative bioavailability of AUC(test)/AUC(zinc gluconate) was 190 %, which showed that the bound zinc in No.LZ-1108 was more bioavailable than zinc gluconate. The present study reports an interesting alternative to developing zinc-based supplements from a natural source of zinc.

Scavenger receptor class B, type I (SR-BI) homo-dimerizes via its C-terminal region: fluorescence resonance energy transfer analysis.

Expression of the scavenger receptor class B, type I (SR-BI) receptor facilitates high density lipoprotein cholesterol transport and correlates with protection against atherosclerosis. Studies have shown that SR-BI self-associates, but many of the techniques used to characterize SR-BI homo-oligomerization were wrought with the prospect of producing artifacts. Therefore, we employed fluorescence resonance energy transfer (FRET) to visualize SR-BI homo-oligomerization with the benefit of gaining information about its quaternary structure in the absence of typical membrane receptor artifacts. To this end, SR-BI was tagged at the N- or C-termini with either cyan (CFP) or yellow (YFP) fluorescent protein. To test whether SR-BI subunits oligomerize through N-N, N-C or C-C terminal interactions, we co-expressed the appropriate SR-BI fusion protein combinations in COS-7 cells and measured live-cell FRET following acceptor photobleaching. We did not observe FRET with co-transfection of SR-BI with CFP and YFP at the N-termini nor at the N- and C-termini, suggesting that the N-termini are not proximal to each other or to the C-termini. However, FRET was observed with co-transfection of SR-BI with CFP and YFP at the C-termini, suggesting that the C-terminal ends are within 10 nm of each other, consistent with SR-BI dimerization via its C-terminal region.

Glycine 420 near the C-terminal transmembrane domain of SR-BI is critical for proper delivery and metabolism of high density lipoprotein cholesteryl ester.

Scavenger receptor BI, SR-BI, is a physiologically relevant receptor for high density lipoprotein (HDL) that mediates the uptake of cholesteryl esters and delivers them to a metabolically active membrane pool where they are subsequently hydrolyzed. A previously characterized SR-BI mutant, A-VI, with an epitope tag inserted into the extracellular domain near the C-terminal transmembrane segment, revealed a separation-of-function between SR-BI-mediated HDL cholesteryl ester uptake and cholesterol efflux to HDL, on one hand, and cholesterol release to small unilamellar phospholipid vesicle acceptors and an increased cholesterol oxidase-sensitive pool of membrane free cholesterol on the other. To further elucidate amino acid residues responsible for this separation-of-function phenotype, we engineered alanine substitutions and point mutations in and around the site of epitope tag insertion, and tested these for various cholesterol transport functions. We found that changing amino acid 420 from glycine to histidine had a profound effect on SR-BI function. Despite the ability to mediate selective HDL cholesteryl ester uptake, the G420H receptor had a greatly reduced ability to: 1) enlarge the cholesterol oxidase-sensitive pool of membrane free cholesterol, 2) mediate cholesterol efflux to HDL, even at low concentrations of HDL acceptor where binding-dependent cholesterol efflux predominates, and 3) accumulate cholesterol mass within the cell. Most importantly, the G420H mutant was unable to deliver the HDL cholesteryl ester to a metabolically active membrane compartment for efficient hydrolysis. These observations have important implications regarding SR-BI function as related to its structure near the C-terminal transmembrane domain.

Scavenger receptor BI (SR-BI) clustered on microvillar extensions suggests that this plasma membrane domain is a way station for cholesterol trafficking between cells and high-density lipoprotein.

Receptor-mediated trafficking of cholesterol between lipoproteins and cells is a fundamental biological process at the organismal and cellular levels. In contrast to the well-studied pathway of LDL receptor-mediated endocytosis, little is known about the trafficking of high-density lipoprotein (HDL) cholesterol by the HDL receptor, scavenger receptor BI (SR-BI). SR-BI mediates HDL cholesteryl ester uptake in a process in which HDL lipids are selectively transferred to the cell membrane without the uptake and degradation of the HDL particle. We report here the cell surface locale where the trafficking of HDL cholesterol occurs. Fluorescence confocal microscopy showed SR-BI in patches and small extensions of the cell surface that were distinct from sites of caveolin-1 expression. Electron microscopy showed SR-BI in patches or clusters primarily on microvillar extensions of the plasma membrane. The organization of SR-BI in this manner suggests that this microvillar domain is a way station for cholesterol trafficking between HDL and cells. The types of phospholipids in this domain are unknown, but SR-BI is not strongly associated with classical membrane rafts rich in detergent-resistant saturated phospholipids. We speculate that SR-BI is in a more fluid membrane domain that will favor rapid cholesterol flux between the membrane and HDL.

Separation of lipid transport functions by mutations in the extracellular domain of scavenger receptor class B, type I.

Scavenger receptor class B, type I (SR-BI) shows a variety of effects on cellular cholesterol metabolism, including increased selective uptake of high density lipoprotein (HDL) cholesteryl ester, stimulation of free cholesterol (FC) efflux from cells to HDL and phospholipid vesicles, and changes in the distribution of plasma membrane FC as evidenced by increased susceptibility to exogenous cholesterol oxidase. Previous studies showed that these multiple effects require the extracellular domain of SR-BI, but not the transmembrane and cytoplasmic domains. To test whether 1) the extracellular domain of SR-BI mediates multiple activities by virtue of discrete functional subdomains, or 2) the multiple activities are, in fact, secondary to and driven by changes in cholesterol flux, the extracellular domain of SR-BI was subjected to insertional mutagenesis by strategically placing an epitope tag into nine sites. These experiments identified four classes of mutants with disruptions at different levels of function. Class 4 mutants showed a clear separation of function between HDL binding, HDL cholesteryl ester uptake, and HDL-dependent FC efflux on one hand and FC efflux to small unilamellar vesicles and an increased cholesterol oxidase-sensitive pool of membrane FC on the other. Selective disruption of the latter two functions provides evidence for multiple functional subdomains in the extracellular receptor domain. Furthermore, these findings uncover a difference in the SR-BI-mediated efflux pathways for FC transfer to HDL acceptors versus phospholipid vesicles. The loss of the cholesterol oxidase-sensitive FC pool and FC efflux to small unilamellar vesicle acceptors in Class 4 mutants suggests that these activities may be mechanistically related.