Tag: dyslipidaemia

Categories : Metabolic Disorders New Compounds and TreatmentsTags :

Controlling Lipid Levels with Less Side Effects Possible with New Drug

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Image Credit: Institute of Transformative Bio-Molecules (ITbM), Nagoya University

Researchers at Nagoya University in Japan have developed a new compound, ZTA-261, that binds to thyroid hormone receptor beta (THRβ). THRβ plays an important role in the regulation of lipid metabolism, which affects lipid levels in the blood. Mice administered the drug showed decreased lipid levels in the liver and blood, with fewer side effects in the liver, heart, and bones compared to existing compounds.  These findings, published in Communications Medicine, suggest that ZTA-261 is an effective treatment for lipid disorders such as dyslipidaemia.

Approximately one in ten people is classified as obese or overweight, often due to abnormalities in lipid metabolism. Abnormal levels of lipids in the blood, known as dyslipidaemia, lead to an increased risk of chest pain, heart attack, and stroke.

There is growing interest in developing treatments for dyslipidaemia that leverage the properties of thyroid hormones. Thyroid hormones increase overall metabolism through binding to two types of receptors: alpha (THRα) and beta (THRβ). The brain, heart, and muscle contain the α-subtype, whereas the liver and pituitary gland primarily express the β-subtype.

Treatments that rely on THR activation face challenges due to the side effects of thyroid hormones. Although THRα regulates cardiovascular functions, excess levels of thyroid hormone lead to adverse effects in nearby organs such as heart enlargement and muscle and bone wasting. On the other hand, activation of THRβ influences lipid metabolism without these severe side effects.

As a result, THRβ has become a desirable target for treating metabolic disorders such as dyslipidaemia. However, common treatments, such as the natural thyroid hormone T3, show almost no selectivity between the α and β receptors, making it difficult to avoid the severe side effects caused by binding to THRα.

To address this problem, a research team, including Masakazu Nambo, Taeko Ohkawa, Ayato Sato, Cathleen Crudden, and Takashi Yoshimura from Nagoya University’s WPI-ITbM, developed ZTA-261, a thyroid hormone derivative drug with a similar structure. To test its efficacy, they compared it with GC-1, another thyroid hormone derivative, and the natural thyroid hormone T3 in a mouse model.

They found that ZTA-261 had almost 100 times higher selectivity for THRβ than THRα. In comparison, GC-1 showed only a 20-fold difference in affinity, showing ZTA-261’s superior selectivity. This was confirmed by the significant increase in heart weight and bone damage indicators in T3-treated mice but not in those treated with ZTA-261.

“Our findings suggest that ZTA-261 is much less toxic than T3 and even less toxic than GC-1, which is known as a THRβ-selective compound,” Ohkawa said. “I find it amazing that the difference in THR beta-selectivity between ZTA-261 and GC-1 – 100 times selectivity versus 20 times selectivity – truly has this big an impact on heart and bone toxicity.”

As many drugs have been discontinued in preclinical trials because of their toxicity in the liver, the researchers checked for potential liver toxicity by measuring alanine aminotransferase (ALT) levels in the blood. Their findings confirmed the safety of the drug, finding no significant differences in ALT levels between mice treated with ZTA-261 and those treated with saline. Although these results are promising, more studies, including human trials, will be necessary before considering ZTA-261 for clinical use. However, this breakthrough represents a significant step forward in the development of safer treatments for lipid disorders.

“ZTA-261 has extremely high affinity and selectivity for THRβ among the thyroid hormone derivatives developed to date,” Nambo explained. “In the process of synthesising a variety of derivatives, we have found that precise molecular design is crucial for both selectivity and affinity. We believe that this study will provide new and important insights into drug discovery.”

Source: Institute of Transformative Bio-Molecules (ITbM), Nagoya Universityy

Categories : Diet and Nutrition Metabolic DisordersTags :

Almonds Help Weight Loss and Improve Cardiometabolic Health

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Photo by Pavel Kalenik on Unsplash

Diets often recommend avoiding nuts as they contain a large amount of fat even though they are high in protein and fibre. Now, a large study published in the journal Obesity demonstrated that including almonds in an energy restricted diet not only helped participants to lose weight, but also improved their cardiometabolic health.

Examining the effects of energy restricted diets supplemented with Californian almonds or with carbohydrate- rich snacks, researchers found that both diets successfully reduced body weight by about 7kg.

Globally, more than 1.9 billion adults are overweight (650 million with obesity). Two in three people (approximately 12.5 million adults) are overweight or have obesity, as do one in every two South Africans.

UniSA researcher Dr Sharayah Carter says the study demonstrates how nuts can support a healthy diet for weight management and cardiometabolic health.

“Nuts, like almonds, are a great snack. They’re high in protein, fibre, and packed with vitamins and minerals, but they also have a high fat content which people can associate with increased body weight,” Dr Carter says.

“Nuts contain unsaturated fats – or healthy fats – which can improve blood cholesterol levels, ease inflammation, and contribute to a healthy heart.

“In this study we examined the effects of an almond-supplemented diet with a nut-free diet to identify any influence on weight and cardiometabolic outcomes.

“Both the nut and nut free diets resulted in approximately 9.3% reduction in body weight over the trial.

“Yet the almond-supplemented diets also demonstrated statistically significant changes in some highly atherogenic lipoprotein subfractions, which may lead to improved cardiometabolic health in the longer term.

“Additionally, nuts have the added benefit of making you feel fuller for longer, which is always a pro when you’re trying to manage your weight.”

The study, funded by the Almond Board of California, had 106 participants complete a 9-month eating program (a three-month energy-restricted diet for weight loss in Phase 1, followed by Phase 2, a six-month energy-controlled diet for weight maintenance). In both phases, 15% of participants’ energy intake comprised unsalted whole almonds with skins (for the nut diet) or 15% carbohydrate-rich snacks – such as rice crackers or baked cereal bars (for the nut-free diet).

Reductions occurred in fasting glucose (−0.2mmol/L), insulin (−8.1pmol/L), blood pressure (−4.9 mmHg systolic, −5.0mmHg diastolic), total cholesterol (−0.3 mmol/L), low-density lipoprotein (LDL) (−0.2mmol/L), very low-density lipoprotein (−0.1mmol/L), and triglycerides (−0.3mmol/L), and high-density lipoprotein increased (0.1mmol/L) by the end of Phase 2 in both groups.

Source: University of South Australia

Categories : Cardiovascular Disease Lab Tests and ImagingTags :

Comprehensive Bloodstream Lipid Level Test Can Predict CVD Decades Early

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Source: Pixabay CC0

Lipidomics, measuring many different bloodstream lipid levels, can predict the risk of developing type 2 diabetes (T2D) and cardiovascular disease (CVD) years in the future, according to a new study in PLOS Biology. Such early prediction through lipidomic profiling may provide the basis for recommending diet and lifestyle interventions before disease develops.

At present, patient history and current risk behaviours are the main predictors for T2D and CVD, along with high- and low-density cholesterol ratios and levels. But there are over one hundred other types of lipids in the blood, which are thought to at least partially reflect aspects of metabolism and homeostasis throughout the body.

Nowadays, it is possible to measure thousands of individual lipids that make up the lipidome. Nuclear magnetic resonance spectrometry (NMR) metabolomics is also being increasingly used in large cohort studies to report on total levels of selected lipid classes, and relative levels of fatty acid saturation.

To find out if detailed lipid profiles could be better predictors, the authors drew on data and blood samples from a longitudinal health study of over 4000 middle-aged participants, first assessed from 1991 to 1994, with follow-up to 2015. Using baseline blood samples, the concentrations of 184 lipids were assessed. During the follow-up period, 13.8% of participants developed T2D, and 22% developed CVD.

The authors performed repeated training and testing on the data to create a risk model. Once the model was developed, individuals were clustered into one of six subgroups based on their lipidomics profile.

Compared to the group averages, the risk for T2D in the highest-risk group was 37%, an increase in risk of 168%. The risk for CVD in the highest-risk group was 40.5%, an increase in risk of 84%. Significant reductions in risk compared to the averages were also seen in the lowest-risk groups. The increased risk for either disease was independent of known genetic risk factors, and independent of the number of years until disease onset.

Rsk could be individually defined decades before disease onset, possibly in time to take steps to avert disease. Lipidomics could be combined with genetics and patient history to provide new insights into the beginnings of the disease. Additionally, new drug candidates could be identified from the lipids  contributing the greatest risk.

“The lipidomic risk, which is derived from only one single mass-spectrometric measurement that is cheap and fast, could extend traditional risk assessment based on clinical assay,” said lead researcher Chris Lauber of Lipotype. “In addition, individual lipids in blood may be the consequences of or contribute to a wide variety of metabolic processes, which may be individually significant as markers of those processes. If that is true, Lauber said, “the lipidome may provide insights much beyond diabetes and cardiovascular disease risk.”

Lauber added: “Strengthening disease prevention is a global joint effort with many facets. We show how lipidomics can expand our toolkit for early detection of individuals at high risk of developing diabetes and cardiovascular diseases.”

Source: EurekAlert!

Categories : Cardiovascular Disease PaediatricsTags :

Cholesterol Screening Recommended for Children with Autism

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Phot by Ben Wicks on Unsplash

Physicians have recommended that children with autism spectrum disorder (ASD) receive screening for abnormally high or low cholesterol levels at least once during their childhood, since ASD is a risk factor for cardiovascular disease in both children and adults.

The recommendation stemmed from a recent study, published in Translational Psychiatry, that found reduced levels of high density lipoprotein cholesterol (HDL-C) in individuals from families with two or more children with ASD. Additionally, they found reduced or elevated levels of other lipids, apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB). Individuals with low HDL-C levels or ApoA1 levels had lower adaptive functioning than other individuals with ASD.

“This latest research is part of our ongoing work to understand some of the co-occurring conditions with ASD,” said Elaine Tierney, MD, a child and adolescent psychiatrist with Kennedy Krieger Institute. “Our work indicates that lipids are abnormal in many individuals with ASD. Our findings, in addition to studies that show an increase in heart disease in individuals with ASD, lead us to recommend that children with ASD be screened for abnormal total and HDL cholesterol levels. We hope our work underscores the importance of cholesterol screening and raises awareness for families in the ASD community.”

Previously, Dr Tierney and colleagues identified that Smith-Lemli-Opitz Syndrome (SLOS), a genetic condition of impaired cholesterol biosynthesis, is associated with autism. This led to a recommendation that all children with ASD be screened for SLOS if they exhibit some of its characteristics, such as slow growth, microcephaly, mental retardation and other birth defects, although the severity of this rare disease can vary.

Source: Kennedy Krieger Institute