MFSD2A

A protein that transports lipid into cells reveals clues to treating a major health problem affecting kidneys. Researchers from Singapore have identified a potential dietary supplement that may improve recovery following acute kidney injury (AKI). The finding, published in the Journal of Lipid Research, comes from a long-running research programme at Duke-NUS Medical School investigating how cells take up a specialised omega-3 lipid called LPC-DHA. A major public health concern, AKI affects an estimated 13.3 million people globally each year and has a mortality rate of 20 to 50 per cent depending on the economic status of the country and stage of the disease. One of the main causes of AKI is ischemic 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 and an MD-PhD student with Duke-NUS' Cardiovascular & Metabolic Disorders (CVMD) Programme. "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 ischemic 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 Professor David Silver, the senior author of the study and Deputy Director of the CVMD Programme. "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.

Omega-3 lysolipids are important for protecting the liver from dietary fat, according to researchers. Long-running research by Duke-NUS Medical School into the omega-3 transporter protein Mfsd2a has shown that it plays a key role in a specific mechanism that prevents the liver from storing too much fat from food. Published in the Journal of Clinical Investigation, this latest study by Duke-NUS and collaborators from Singapore General Hospital (SGH) signals the possibility that a dietary supplement could be developed to help prevent non-alcoholic fatty liver disease (NAFLD). Eating too much fatty food increases the risk of many health problems, including cardiovascular disease, obesity, diabetes and NAFLD. The excess fat that accumulates in the liver during the onset of NAFLD leads to inflammation and progressive deterioration and scarring, called cirrhosis of the liver. The rate of NAFLD is remarkably high in Singapore, affecting around 40 per cent of adults compared to 27 per cent globally. One typeof fat called phospholipids are essential for making cell membranes and actually protect the liver against the harmful effects of dietary fat. "For over a decade, the researchers at Duke-NUS have been studying Mfsd2a, which transports the phospholipid lysophosphatidyl choline (LPC) into cells," said Dr Chin Cheen Fei, first author of the study and Research Fellow with Duke-NUS' Cardiovascular & Metabolic Disorders (CVMD) Programme. "In this latest work, we set out to determine if LPC transport into the liver by Mfsd2a is an important source for liver phospholipids and a means of protecting the liver against NAFLD." The team embarked on studies using preclinical and isolated samples of human liver. They focused on the effect of a variety of measures that altered the activity of Mfsd2a and its uptake of specific lipids. "Our findings show that LPC lipids, particularly those containing polyunsaturated fatty acids such as omega-3 fatty acid DHA, could become a means of long-term prevention for NAFLD," said Dr George Goh, Senior Consultant at SGH and one of the collaborators of the study. "Our study is the first to suggest the potential of dietary LPC supplementation in protecting the liver against damage caused by a high-fat diet." The researchers noted that the liver has a significant demand for phospholipids in general, which increases when challenged with fatty foods. NAFLD takes years to develop and can progress to non-alcoholic steatohepatitis and cirrhosis, so supplements taken over that period could offer protection. "Our study emphasises the importance of taking a proactive approach to keeping the liver healthy," said Professor David Silver, the senior author of the study and Deputy Director of the CVMD Programme. "Overnutrition with fatty foods can cause cardiovascular disease, obesity, diabetes and NAFLD. The prevalence of NAFLD is of major importance to the general population, which is becoming increasingly aware of this problem." As the discovery marks a significant development in the search for a way to protect liver function from a disease that is affecting a growing number of people across the world, the Duke-NUS research team now plans to undertake rigorous clinical studies with their collaborators at SGH to test whether LPC supplementation really can improve the outcomes in patients with NAFLD. "If the trials prove successful, this work could help the vast numbers of people worldwide whose health is seriously affected by the condition," said Prof Silver. Next, the team plans to probe in more detail the molecular mechanisms that allow LPCs to promote liver health in general.

Researchers have developed a zebrafish model that provides new insight into how the brain acquires essential omega-3 fatty acids, including docosahexaenoic acid (DHA) and linolenic acid (ALA), with the potential to improve understanding of lipid transport across the blood-brain barrier and of disruptions in this process that can lead to birth defects or neurological conditions. Researchers at the UCLA David Geffen School of Medicine, the Howard Hughes Medical Institute at UCLA and the National Institutes of Health have developed a zebrafish model that provides new insight into how the brain acquires essential omega-3 fatty acids, including docosahexaenoic acid (DHA) and linolenic acid (ALA). Their findings, published in Nature Communications,have the potential to improve understanding of lipid transport across the blood-brain barrier and of disruptions in this process that can lead to birth defects or neurological conditions. The model may also enable researchers to design drug molecules that are capable of directly reaching the brain. Omega-3 fatty acids are considered essential because the body cannot make them and must obtain them through foods, such as fish, nuts and seeds. DHA levels are especially high in the brain and important for a healthy nervous system. Infants obtain DHA from breastmilk or formula, and deficiencies of this fatty acid have been linked to problems with learning and memory. To get to the brain, omega-3 fatty acids must pass through the blood-brain barrier via the lipid transporter Mfsd2a, which is essential for normal brain development. Despite its importance, scientists did not know precisely how Mfsd2a transports DHA and other omega-3 fatty acids. In the study, the research team provides images of the structure of zebrafish Mfsd2a, which is similar to its human counterpart. The snapshots are the first to detail precisely how fatty acids move across the cell membrane. The study team also identified three compartments in Mfsd2a that suggest distinct steps required to move and flip fatty acids through the transporter, as opposed to movement through a linear tunnel or along the surface of the protein complex. The findings provide key information on how Mfsd2a transports omega-3 fatty acids into the brain and may enable researchers to optimize drug delivery via this route. The study also provides foundational knowledge on how other members of this transporter family, called the major facilitator superfamily (MFS), regulate important cellular functions. The study was led by Tamir Gonen, Ph.D., of UCLA and Doreen Matthies, Ph.D., of NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Additional funding for the study was provided by NIH's National Institute of General Medical Sciences (NIGMS) and the Howard Hughes Medical Institute.