Visual Abstract

Matthias Schittmayer
Dec 1, 2020; 19:2104-2114
Research

Oktawia Nilsson
Nov 17, 2020; 0:jlr.RA120000920v1-jlr.RA120000920
Research Articles

Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) is essential for the transportation of cholesterol between peripheral tissues and the liver. However, specific mutations in Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) are responsible for a late-onset systemic amyloidosis, the pathological accumulation of protein fibrils in tissues and organs. Carriers of these mutations do not exhibit increased cardiovascular disease risk despite displaying reduced levels of ApoA-I/ HDL-cholesterol. To explain this paradox, we show that the HDL particle profile of patients carrying either L75P or L174S ApoA-I amyloidogenic variants a higher relative abundance of the 8.4 nm vs 9.6 nm particles, and that serum from patients, as well as reconstituted 8.4 and 9.6 nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogen-deuterium exchange revealed that the variants in 8.4 nm rHDL have altered secondary structure composition and display a more flexible binding to lipids compared to their native counterpart. The reduced HDL-cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles and better cholesterol efflux due to altered, region-specific protein structure dynamics.

Nonsmall cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. While mutations in Kras and overexpression of Myc are commonly found in patients, the role of altered lipid metabolism in lung cancer and its interplay with oncogenic Myc is poorly understood. Here we use a transgenic mouse model of Kras-driven lung adenocarcinoma with reversible activation of Myc combined with surface analysis lipid profiling of lung tumors and transcriptomics to study the effect of Myc activity on cholesterol homeostasis. Our findings reveal that the activation of Myc leads to the accumulation of cholesteryl esters (CEs) stored in lipid droplets. Subsequent Myc deactivation leads to further increases in CEs, in contrast to tumors in which Myc was never activated. Gene expression analysis linked cholesterol transport and storage pathways to Myc activity. Our results suggest that increased Myc activity is associated with increased cholesterol influx, reduced efflux, and accumulation of CE-rich lipid droplets in lung tumors. Targeting cholesterol homeostasis is proposed as a promising avenue to explore for novel treatments of lung cancer, with diagnostic and stratification potential in human NSCLC.

Despite the crucial function of the small intestine in nutrient uptake our understanding of the molecular events underlying the digestive function is still rudimentary. Recent studies demonstrated that enterocytes do not direct the entire dietary triacylglycerol toward immediate chylomicron synthesis. Especially after high-fat challenges, parts of the resynthesized triacylglycerol are packaged into cytosolic lipid droplets for transient storage in the endothelial layer of the small intestine. The reason for this temporary storage of triacylglycerol is not completely understood. To utilize lipids from cytosolic lipid droplets for chylomicron synthesis in the endoplasmic reticulum, stored triacylglycerol has to be hydrolyzed either by cytosolic lipolysis or lipophagy. Interestingly, triacylglycerol storage and chylomicron secretion rates are unevenly distributed along the small intestine, with the proximal jejunum exhibiting the highest intermittent storage capacity. We hypothesize that correlating hydrolytic enzyme activities with the reported distribution of triacylglycerol storage and chylomicron secretion in different sections of the small intestine is a promising strategy to determine key enzymes in triacylglycerol remobilization. We employed a serine hydrolase specific activity-based labeling approach in combination with quantitative proteomics to identify and rank hydrolases based on their relative activity in 11 sections of the small intestine. Moreover, we identified several clusters of enzymes showing similar activity distribution along the small intestine. Merging our activity-based results with substrate specificity and subcellular localization known from previous studies, carboxylesterase 2e and arylacetamide deacetylase emerge as promising candidates for triacylglycerol mobilization from cytosolic lipid droplets in enterocytes.

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In five northern U.S. states, black students comprise more than a fifth of ELL enrollment.

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In five northern U.S. states, black students comprise more than a fifth of ELL enrollment.

The College Football Playoff Selection Committee has released its second set of rankings, and Clemson football's moved up to No. 20 following a 24-14 win over Virginia Tech. Starting at No. 23 in last week’s CFP rankings, the Tigers’ latest rise highlights thei

Countries today endorsed a set of wide-reaching guidelines that will boost the already vital [...]

The first in a series of Conference side events, the high-level panel on Small Island Developing States (SIDS) was held on Saturday. The aim of this event was to present [...]

Rome - The Food and Agriculture Organization of the United Nations (FAO) and Grow Asia, a multi-stakeholder partnership platform that brings together farmers, the private sector, governments, [...]

Travel to Oregon, Minnesota, North Dakota and Rhode Island to see beautiful autumn foliage and much more. --- For more videos from Smithsonian Magazine: https://www.smithsonianmag.com/videos/ Digital Editorial Director: Brian Wolly Supervising Producer & Scriptwriter: Michelle Mehrtens Video Editor: Sierra Theobald

From charming streets to stunning scenery, consider Hawaii, Idaho, Massachusetts, or New York for your next summer adventure. --- For more videos from Smithsonian Magazine: https://www.smithsonianmag.com/videos/ Digital Editorial Director: Brian Wolly Supervising Producer & Scriptwriter: Michelle Mehrtens Producer: Nicki Marko Producer: Sierra Theobald Editor: Michael Kneller

This spring, take a break and smell the flowers in New Mexico, Kansas, California and New Jersey. --- For more videos from Smithsonian Magazine: https://www.smithsonianmag.com/videos/ Digital Editorial Director: Brian Wolly Supervising Producer & Scriptwriter: Michelle Mehrtens Video Editor: Sierra Theobald

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A special committee has until January 15 to finalize the design, location and funding for a monument that will be erected on the lawn of the South Carolina State House

The Town of Kensington, P.E.I., has committed to implementing a new campaign to end gender-based violence.

A heartfelt initiative is taking root in some small towns across eastern Ontario where light and hydro poles are being adorned with banners that pay tribute to local veterans.

After Canada Post workers gave a 72-hour notice to strike early Tuesday, some Calgary business owners are worried about what this means for holiday season sales. 

She only came for a week, but impacted lives of several families with children with autism. Isabel Black shares about her experiences in Montenegro.

SolidWorks CAD Software Enables Engineering Students to Fit ‘CubeSat’ Components Into a Four-Inch Square Box

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Thousands of Highmark 2019 plan participants and groups to receive checks After announcing a reduction of Delaware Health Insurance Marketplace rates for the upcoming enrollment year, Insurance Commissioner Trinidad Navarro has more good news for residents who purchase insurance on the Delaware Health Insurance Marketplace, those who purchase Highmark Blue Cross Blue Shield Delaware plans […]

Highmark plan participants and groups to receive checks Insurance Commissioner Trinidad Navarro announced today that Highmark Blue Cross Blue Shield Delaware will issue rebates totaling over $12.3 million to some Delawareans. Residents who purchase insurance on the Delaware Health Insurance Marketplace, those who purchase Highmark Delaware plans outside of the marketplace, and Highmark small group […]

Following in-depth reviews by independent actuaries and the Office of Value-Based Health Care Delivery, rates for regulated 2023 health, dental, and small group insurance plans were announced today. While premiums are rising steeply across the country, the extension of consumer-friendly subsidies through the Inflation Reduction Act, coupled with Delaware’s strong 2022 enrollment and 2023 Health Insurance Marketplace expansion, will limit consumer impact locally.

Delaware Division of Small Business and Delaware Black Chamber of Commerce Announce Partnership Dover, DE (Nov. 18, 2020) – More small businesses will have help in applying for DE Relief Grants through a new relationship between the Delaware Division of Small Business (DSB) and the Delaware Black Chamber of Commerce (DEBCC). The two organizations have […]

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DOVER, DE – After a difficult year for Delaware small businesses, the Division of Small Business is re-starting EDGE Grants, an innovative, competitive program to provide young Delaware companies with funds to help them expand their business. EDGE (Encouraging Development, Growth and Expansion) grows Delaware’s economy by providing funding to promising early-stage businesses to level […]

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DOVER, DE (September 1, 2021) – Young Delaware companies in need of funding to help expand their business can now apply to compete for an Encouraging Development, Growth and Expansion (EDGE) Grant from the Division of Small Business. The division will be accepting EDGE Grant applications until September 30 from promising early-stage businesses throughout Delaware. […]

WILMINGTON, Del. – Small businesses and nonprofit organizations in New Castle County affected by flooding from Hurricane Ida earlier this month are now eligible to apply for an Economic Injury Disaster Loan from the U.S. Small Business Administration (SBA). Eligible businesses and nonprofits may qualify for loans up to $2 million. The SBA Economic Injury […]

MIDDLETOWN, Del. (December 16, 2021) – The Delaware Division of Small Business recognized 15 small businesses Thursday as winners of the fourth round of Encouraging Development, Growth and Expansion (EDGE) Grants. Awardees in the latest round of the competition include a company working to alleviate phantom limb pain for amputees, a maker of easy-to-use diagnostic […]

The Delaware Division of Small Business is now accepting applications for the Site Readiness Fund from qualified businesses or local governments. Established through Senate Bill 127, the fund promotes economic growth and stability by investing in the development or improvement of commercial and industrial sites to attract job-creating businesses. The Site Readiness Fund provides grants, […]

WILMINGTON, Del. – Governor John Carney and the Delaware Division of Small Business announced Thursday more than $7.7 million in funding awards to seven organizations as part of the recovery effort for the travel, tourism, and outdoor recreation industries.  The funds are part of the Economic Development Administration’s (EDA) $750 million American Rescue Plan Travel, Tourism […]

DOVER, DE (March 1, 2022) – Young Delaware companies in need of funding to help expand their business can now apply to compete for an Encouraging Development, Growth and Expansion (EDGE) Grant from the Division of Small Business. The division will be accepting EDGE Grant applications until March 31 from promising early-stage businesses throughout Delaware. […]

DOVER, Del. – The Delaware Division of Small Business launched SizeUpDelaware this week, making powerful market research and business intelligence available to small businesses to help them succeed. Small business owners in Delaware can now access industry-specific and hyperlocal information to help them grow and make smarter decisions using Big Data analysis. The research is individually […]