Tag: lipids

Categories : Cardiovascular DiseaseTags :

CVD and Obesity: When Protective Lipids Decline, Health Risks Increase

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The mesenteric arteries from obese and lean mice, pictured above, supply oxygen and nutrients to the intestines. Immunofluorescence staining revealed that the NOGO-B protein increases in the vascular walls of mice fed a high fat diet compared to mice fed a standard diet. As a result, ceramides decrease in the mesenteric arteries of the obese mice, damaging endothelial cells lining blood vessels. Credit: Annarita Di Lorenzo/Weill Cornell Medicine

New research from Weill Cornell Medicine has uncovered a surprising culprit underlying cardiovascular diseases in obesity and diabetes—not the presence of certain fats, but their suppression. The study, published in Nature Communications, challenges the conventional belief that a type of fat called ceramides accumulates in blood vessels causing inflammation and health risks. Instead, their findings reveal that when ceramides decrease in endothelial cells lining blood vessels, it can be damaging and cause chronic illnesses. Ironically, the findings could ultimately lead to therapies that maintain high levels of these protective lipids in patients with obesity.

Ceramides are found throughout the body and in the endothelium, the thin lining inside blood vessels. These waxy lipids regulate blood vessel tone, dilating or contracting vessels to modulate blood pressure. They also help prevent blood clots, keeping blood flowing easily through the body’s extensive highway of arteries and veins.

“The common assumption in the field was that high levels of ceramides in the endothelium of blood vessels contributed to cardiovascular disease, but this conclusion was extrapolated from in vitro data in cells,” said Dr Annarita Di Lorenzo, professor of pathology and laboratory medicine at Weill Cornell Medicine. “Ours is the first in vivo study that measures the levels of the lipids in the endothelial cells of an animal model. In obese mice fed a high-fat diet, ceramides do not build up—they decrease compared to lean mice.” Also working on this research are co-first authors Dr Onorina L. Manzo, postdoctoral associate and Luisa Rubinelli, both in Dr Di Lorenzo’s lab.

Ceramide to the Rescue

Dr Di Lorenzo and her team discovered the importance of ceramides in blood vessels two years ago. Together with Dr Giuseppe Faraco, assistant professor of neuroscience at Weill Cornell Medicine, they found that decreased levels of ceramides in otherwise healthy mice causes severe blood vessel inflammation in the brain, clot formation and death. Last year, the team reported that ceramide production increases as a protective response in a mouse model of coronary artery disease. Ultimately, when ceramide is broken down by the body it produces a compound called sphingosine-1-phosphate (S1P), which builds up and protects mice against cardiovascular disease. But when this process doesn’t work the mice are left vulnerable.

The researchers also found that two proteins, Nogo-B and ORMDL, decreased the production of ceramides and S1P in obesity. This decrease leads to increased blood pressure, impaired vascular regulation and higher glucose levels—all of which contribute to cardiometabolic conditions that affect the heart (cardiovascular system) and energy processing (metabolism), like diabetes like diabetes, hypertension, coronary artery disease and stroke.

Maintaining Balance

To understand how these different molecules interact, the researchers tested what happens in animal models. Mice with obesity fed a high-fat diet had low levels of ceramides and S1P, but high levels of Nogo-B. These mice showed signs of inflammation, diabetes and high blood pressure.

But what happens if the Nogo-B inhibitor wasn’t present? The researchers knocked out Nogo-B only in the endothelium of blood vessels in a mouse model to find out. “These mice have the same body weight and diabetes as controls, but their blood vessel health is much better,” said Dr. Di Lorenzo. “By knocking out this inhibitor, we preserved vascular health. This also showed that the regulation of ceramide metabolism causes vascular dysfunction and inflammation in obesity.”

The paper suggests that targeting this metabolic pathway could have multiple beneficial effects in the treatment of cardiometabolic diseases related to obesity. “Nogo suppresses biosynthesis of ceramides, so if we can identify a drug that can block Nogo-B, we could restore ceramide levels to a healthy balance and this would fight not only obesity and diabetes, but would directly keep blood vessels functioning properly,” she said.

Source: Weill Cornell Medicine

Categories : Metabolic DisordersTags :

In Type 2 Diabetics, Toxic Lipids and a Beneficial One Surge at Certain Times

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Credit: Cell Reports Medicine (2023).

While sugar is most frequently blamed in the development of type 2 diabetes, a better understanding of the role of fats is also essential. By analysing the blood profiles of dozens of people suffering from diabetes or pre-diabetes, or who have had their pancreas partially removed, researchers at the University of Geneva (UNIGE) and Geneva University Hospitals (HUG) have made two major discoveries.

Firstly, the lipid composition of blood and adipose tissues fluctuates during the day, and is altered in a day-time dependent manner in diabetics, who have higher levels of toxic lipids. In addition, one type of lipid, lysoPI, is capable of boosting insulin secretion when the beta cells that normally produce it fail. These results, published in the journals Cell Reports Medicine and Diabetes, may have important implications for the treatment of diabetic patients.

The role of lipids in the physiological and pathological processes of human metabolism is gradually becoming clearer, particularly in type 2 diabetes, one of the most widespread serious metabolic disorders. Thanks to cutting-edge tools, in particular mass spectrometry, researchers are now able to simultaneously measure the levels of several hundred different types of lipids, each with its own specific characteristics and beneficial or harmful effects on our metabolism.

‘‘Identifying which lipids are most present in type 2 diabetics could provide a basis for a wide range of interventions: early detection, prevention, potential therapeutic targets or personalised recommendations – the possibilities are immense,’’ says Charna Dibner, a professor in the Department of Surgery and a specialist in circadian rhythms in metabolic disorders, . ‘‘This is why we carried out a detailed analysis of the blood profiles of patients recruited in four European countries and confirmed some of our results on a mouse model of the disease.’’

Dibner led the studies along with Pierre Maechler, a professor in the Department of Cell Physiology and Metabolism, at the UNIGE Faculty of Medicine, and members of the Diabetes Faculty Centre.

Chronobiology to better identify diabetes

The team carried out a ‘‘lipidomic’’ analysis of two groups of patients in order to establish the profile, over a 24-hour cycle, of multiple lipids present in the blood and adipose tissues. ‘‘The differences between the lipid profiles of type 2 diabetics and people without diabetes are particularly pronounced in the early morning, when there is an increase in certain toxic lipids,’’ explains Dibner. ‘‘Why? We don’t know yet. But this could be a marker of the severity of diabetes and paves the way for personalised care according to each patient’s specific chronotype.”

And implications go beyond diabetes: if samples are taken at very different times of the day, the results can be distorted and give contradictory results. ‘‘It’s the same thing in the clinic: an examination carried out in the morning or evening, or a treatment taken at different times, can have an impact on diagnosis and even on the effectiveness of treatments.’’

A crutch for beta cells

Charna Dibner and Pierre Maechler extended their lipidomic analyses to include not only people with type 2 diabetes but also a mouse model of pre-diabetes and patients who had lost around half their insulin-producing beta cells after a surgery. ‘‘We discovered that a type of lipid, lysoPIs, increases when there is a sharp decrease in functional β cells, even before the onset of clinical symptoms of diabetes.’’

The scientists then administered lysoPI to diabetic mice and observed an increase in insulin production. ‘‘The same phenomenon occurred in vitro, on pancreatic cells from diabetic patients,’’ adds Pierre Maechler. ‘‘The lysoPIs therefore have the capacity to reinforce insulin secretion by acting as a crutch when the number of beta cells decreases or when these cells malfunction. Yet, certain foods, such as legumes, naturally contain lysoPI precursors.’’

By bringing to light the unsuspected role of lysoPIs, researchers will be able to explore new avenues opened by their discoveries. The development of dietary supplements or even molecules specific to lysoPI receptors could be an interesting strategy for controlling diabetes, as could taking better account of the chronobiological profiles of patients. Diabetes is a complex disease that calls for much more personalised management than is currently the case.

Source: University of Geneva

Categories : Diet and Nutrition Injury & TraumaTags :

Specialised Omega-3 Lipid Could be a New Treatment for Acute Kidney Injury

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Photo by Robina Weermeijer on Unsplash

Researchers from Singapore have identified a potential dietary supplement of omega-3 that may improve recovery following acute kidney injury (AKI). The finding, published in the Journal of Lipid Research, may offer a new way to treat this serious condition, which currently has few therapies.

The study was part of a long-running research programme at Duke-NUS Medical School investigating how cells take up a specialised omega-3 lipid called LPC-DHA.

AKI affects some 13.3 million people globally each year, with a mortality rate of 20 to 50% depending on the economic status of the country and stage of the disease. One of the main causes of AKI is ischaemic reperfusion injury, which occurs when the kidney’s blood supply is restored after a period of restricted blood flow and poor oxygen delivery due to illness, injury or surgical intervention. In particular, it damages a crucial part of the kidney called the S3 proximal tubules that regulate the levels of absorption of water and soluble substances, including salts.

“AKI is a serious health problem with limited treatment options,” said Dr Randy Loke, first author of the study. “We sought to understand how these tubules repair themselves and found that the activity of the protein Mfsd2a, which transports LPC-DHA into cells, is a key factor influencing the rate of recovery of kidney function after ischaemic reperfusion injury.”

In their study, the researchers discovered that preclinical models with reduced levels of Mfsd2a showed delayed recovery, increased damage and inflammation after kidney injury. However, when these models were treated with LPC-DHA, their kidney function improved and the damage was reduced. LPC-DHA also restored the structure of the S3 proximal tubules, helping them function properly again.

“While more research is needed, the potential of LPC-DHA as a dietary supplement is exciting for future recipients who have suffered from AKI,” said senior study author Professor David Silver. “As our results suggest that LPC-DHA could become a safe and effective treatment that offers lifelong protection, its potential can help protect the kidneys and aid in recovery for these individuals.”

In the next phase, the research team plans to continue investigating the beneficial functions of LPC in the kidney and are aiming to initiate clinical testing of LPC supplements to determine their effectiveness in improving renal function and recovery following AKI in patients.

They also plan to continue their investigations of the protein Mfsd2a to learn more about its role in LPC transport and its involvement in diseases affecting other tissues and organs. Previous research by Prof Silver’s group, with collaborators from other institutions, have already highlighted the significance of the protein’s LPC-transporting activities in diseases of other organs, including the liver, lungs and brain.

Source: Duke–NUS Medical School

Categories : Metabolic DisordersTags :

High Lipid Levels Even More Damaging than Previously Believed

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Blood sample being drawn
Photo by Hush Naidoo Jade Photography on Unsplash

High lipid levels in people with type 2 diabetes and obesity are more harmful than previously thought, according to findings from a new study which found that stressed cells can damage nearby cells.

In patients with metabolic diseases, elevated lipid levels in the blood create stress in muscle cells – a reaction to changes outside the cell which damage their structure and function.

The study, published in Nature Communications, shows that these stressed-out cells give off a signal which can be passed on to other cells.

The signals, known as ceramides, may confer a short-term protective benefit, because they are part of a mechanism designed to reduce stress in the cell. But in long term conditions such as metabolic diseases, the signals can actually kill the cells and worsen symptoms and the illness.

High lipid levels have long been known to damage tissues and organs, contributing to the development of cardiovascular and metabolic diseases including type 2 diabetes, a condition which can be caused by obesity.

Professor Lee Roberts, who supervised the research, said: “Although this research is at an early stage, our discovery may form the basis of new therapies or therapeutic approaches to prevent the development of cardiovascular and metabolic diseases such as diabetes in people with elevated blood fats in obesity.”

In the lab, the team replicated the blood lipid levels observed in humans with metabolic disease by exposing skeletal muscle cells to palmitate, a fatty acid. The cells began to transmit the ceramide signal.

When these cells were mixed with others which had not been previously exposed to lipids, the researchers found that they communicated with each other, transporting the signal in packages called extracellular vesicles.

The experiment was reproduced in human volunteers with metabolic diseases and gave comparable results. The findings provide a completely new angle on how cells respond to stress, with important consequences for our understanding of certain metabolic diseases including obesity.

Professor Roberts said: “This research gives us a novel perspective on how stress develops in the cells of individuals with obesity, and provides new pathways to consider when looking to develop new treatments for metabolic diseases.

“With obesity an ever-increasing epidemic, the burden of associated chronic disease such as type 2 diabetes necessitates new treatments. We hope the results of our research here open a new avenue for research to help address this growing concern.”

Source: University of Leeds