Engineered vegetables target intestinal lipids, improve cholesterol

Researchers at the University of California, Los Angeles, used a new genetically engineered tomato to act as high-density lipoproteins and reduce the negative effects of certain intestinal lipids (unsaturated lysophosphatidic acids, or LPAs) directly correlated with atherosclerosis. They found that the previously ignored LPAs have an important role — inducing alterations in small intestine gene expression and changes in cholesterol levels (increases in low-density lipoproteins and decreases in HDL) and a proinflammatory effect (increases in blood markers of inflammation). They designed genetically engineered tomatoes to produce a peptide, 6F, that mimics the action of apoA-1. When fed to mice, the tomatoes prevented the increase of LPAs in the small intestine and stopped the emergence of the imbalance between HDL and LDL. Alan Fogelman, director of the atherosclerosis research unit at the David Geffen School of Medicine at UCLA, said: “Recognizing the importance of these minor lipids in the small intestine may lead to ways to reduce their levels and prevent abnormalities in blood levels of good and bad cholesterol that contribute to heart attack and stroke.”

Fat and memory loss

Neuroscientists at the Rush University Medical Center, in collaboration with the National Institutes of Health, published a study in the journal Cell Reports indicating that a protein involved in fat metabolism within the liver also stimulates cyclic AMP response element-binding protein, known as CREB, an essential regulator of memory-related proteins. The protein involved is peroxisome proliferator-activated receptor alpha, or PPAR-a,which is highly expressed in the liver and involved in the local fat metabolism processes. “We are surprised to find a high level of PPAR-a in the hippocampus of animal models,” said Kalipada Pahan, professor of neurology at the Rush University Medical Center. Using a bone marrow chimera technique, the researchers created mice with normal PPAR-a in the liver but with depleted levels in the brain, leading to poor memory and learning. These problems were not seen in mice with normal PPAR-a in the brain and no PPAR-a in the liver. In people with excess abdominal fat, PPAR-a is depleted first in the liver and then in the whole body, including the brain, leading to suppressed CREB levels and a higher risk of developing dementia. “Further research must be conducted to see how we could potentially maintain normal PPAR-a in the brain in order to be resistant to memory loss,” Pahan said.

Increasing beneficial high-density lipoprotein

Massachusetts General Hospital researchers published in the Nov. 20 issue of the journal Science Translational Medicine their strategy to increase high-density lipoprotein by targeting certain microRNAs and blocking their action. Two related microRNAs, miR-33a and miR-33b, inhibit a protein, ABCA1, which is essential for making HDL and delivering lipids to the liver. The microRNAs have redundant effects, making it inefficient to block only miR-33a or miR-33b. The researchers used an eight-nucleotide anti-microRNA targeting only the “seed” sequence shared among the miR-33 family members in obese and insulin-resistant African green monkeys. The result was an HDL increase of 40 percent and enhanced expression of ABCA1 and other proteins known to be inhibited by miR-33 family members. “In addition to supporting this strategy for the treatment of cardiovascular disease, our study shows the importance of targeting multiple microRNA family members that may act redundantly to achieve therapeutic efficacy,” says Anders Näär, a professor of cell biology at Harvard Medical School and the leader of this study.

Reading the pancreas through the eye

An innovative method to study the physiopathology of diabetes has been found by Karolinska Institutet researchers. The results are published in the November issue of the journal Proceedings of the National Academy of Sciences, and they show that the scientists may have overcome the obstacle of studying how the Islets of Langerhans really work. “What we’ve done is made the cells optically accessible by grafting a small number of 'reporter islets' into the eyes of mice, which allows us to monitor the activity of the pancreas just by looking into the eye,” says Per-Olof Berggren, professor of experimental endocrinology at the Karolinska Institutet’s Department of Molecular Medicine and Surgery and director of the Rolf Luft Research Centre for Diabetes and Endocrinology. The observations, made over several months, showed that the functional and morphological changes that occur in the pancreas are identical to those appearing in the “reporter islets.” The Islets of Langerhans can, in this manner, be studied to better adapt and personalize pharmacological and nutritional therapies.

Researchers demonstrate efficient method for converting fat cells to liver cells

Stanford University School of Medicine scientists have found a way to turn adipose cells obtained from routine liposuction procedures into liver cells. Using a technique called spherical culture, the team obtained induced hepatocytes, or i-Heps, from adipose stem cells in nine days with an efficiency of 37 percent. This is a significant improvement over previously attempted methods, like the use of induced pluripotent stem cells, also known as iPS, which take much longer to obtain and have a smaller efficiency. But most importantly, the iPS technique had the highly unlikable side effect of tumor growth, which did appear with i-Heps. The experiments were conducted on bioengineered mice with impaired immunity and altered liver cells, which would turn gancyclovir into a potent toxin. When the mice received gancyclovir, their liver cells died and were replaced with 5 million i-Heps through an ultrasound-guided injection. The i-Heps previously been had obtained from spherical cultures of hepatocytes. The harvested adipose stem cells are cultured in a liquid suspension, in which they form spheroids. Four weeks after the procedure, human serum albumin was found in the mice’s blood, indicating that the injected i-Heps were functioning as human liver cells. “We believe our method will be transferable to the clinic,” said Gary Peltz, professor of anesthesia and the senior author of the study. “And because the new liver tissue is derived from a person’s own cells, we do not expect that immunosuppressants will be needed.” This study was published Oct. 21 in the journal Cell Transplantation.

Mitochondrial superoxide may be beneficial to the diabetic kidney

Fundamentally changing previous views on the development of kidney damage in diabetes, a new study published in The Journal of Clinical Investigation finds that caloric excess inhibits mitochondrial processes, leading to cellular damage. Researchers at the University of California, San Diego, School of Medicine describe lower-than-normal superoxide levels and suppressed mitochondrial activity in the damaged kidneys of diabetic mice. The kidney disease markedly declined when the scientists activated a key mitochondrial energy-sensing enzyme called AMPK, leading to increases in superoxide production. Weight loss and exercise are simple methods of increasing beneficial AMPK, but researchers also are developing AMPK agonists. “Mitochondrial superoxide does not seem to be a causative factor of diabetic kidney disease,” said Kumar Sharma, professor of medicine and director of the Center for Renal Translational Medicine at UCSD. “Indeed, when mitochondrial superoxide is increased with AMPK activation, there is reduced kidney disease, suggesting that improving mitochondrial function and superoxide production is actually beneficial for diabetic complications. This idea is a sea change in the field of diabetic complications.”
 
Teodora DonisanThis news roundup was compiled by ASBMB Today contributor Teodora Donisan (teodora.donisan@gmail.com), a medical student at Carol Davila University in Bucharest, Romania. Send links of interest to asbmbtoday@asbmb.org for possible inclusion in future issues.

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