New drug shows promise in mice

For this study, researchers engineered a nanogel-based carrier to deliver a drug directly to the liver.

Dr. S. Thai Thayumanavan, distinguished professor of chemistry and biomedical engineering, department head of biomedical engineering, director of the Center for Bioactive Delivery at the University of Massachusetts Amherst, and lead author of this study explained to Medical News Today:

“Our nanogels have an inherent propensity to home in the liver and then there is a specific need for targeting the hepatocytes in the liver when it comes to metabolic disorders. Therefore, we decorated these nanogels with additional chemical functionalities such that they will not only prefer to home in on the liver but also will be taken up by hepatocytes of the liver.”

The drug Dr. Thayumanavan and his team used in this study is a thyromimetic — a drug that mimics synthetic thyroid hormone.

“The drug is thought to target the thyroid hormone receptor beta, which is found throughout the body but predominantly in the liver,” he said.

“Our drug’s interaction with this receptor is responsible for activating a number of physiological responses, including fatty acid oxidation and reverse cholesterol pathway (RCT), which may be the cause of the observed weight loss and lowering of cholesterol,“ explained Dr. Thayumanavan. “However, much more work needs to be done to confirm this hypothesis.”

Dr. Thayumanavan further noted that thyroid hormone mimics have been previously tested as cholesterol-lowering agents and are currently in clinical trials for the treatment of nonalcoholic steatohepatitis (NASH).

However, he said there have historically been two major issues — the bioavailability of these drugs and possible off-target effects when these thyromimetics reach other organs.

“Thyroid hormone mimics that are being tested in the clinic for NASH — and which are doing quite well — are of low potency so you’re not getting the full potential of the drug,” Dr. Thayumanavan continued. “Our thinking was that by combining a potent thyromimetic with our nanogel, we could eliminate toxicity associated with systemic exposure and gain activity by concentrating the drug at the site we wanted.”

To conduct the study, Dr. Thayumanavan used a group of mice that were fed a high-fat, high-sugar, high-cholesterol diet for 10 weeks, resulting in their weight doubling. There was also a control group of mice fed a healthy diet during those same 10 weeks.

The obese mice were given the thyromimetic drug inside the nanogel-based carrier via intraperitoneal injection every day for 5 weeks.

At the end of the 5 weeks, researchers discovered the mice with obesity had returned to their previous weight, even if their high-fat diet continued.

Additionally, the mice given the drug experienced drops in their cholesterol levels and improvement in liver inflammation.

“We were confident that this approach would help improve the metabolic profile in the mice, such as cholesterol-lowering and reducing fatty liver,” Dr. Thayumanavan said.

“We were very surprised and excited to see the impact this had on body weight reduction. Although thyroid hormone mimics do lower weight, this usually comes with other side effects, which we did not see at all. Our drug appears to be very safe with no adverse effects.”

– Dr. S. Thai Thayumanavan

After reviewing this study, Dr. Rigved Tadwalkar, a board-certified cardiologist at Providence Saint John’s Health Center in Santa Monica, CA, not involved in the research, told MNT his first reaction was one of excitement, but also caution because it is an early phase study.

“The reason for the excitement is that we know that obesity and high cholesterol are significant risk factors for a whole range of cardiovascular diseases, […] but they’re complex and they often require multifaceted management strategies to help improve them that include lifestyle modifications, dietary interventions, physical activity, and then in many cases, to be honest, pharmacologic interventions,” he continued.

“So what’s interesting about this is that we’re essentially targeting an organ to work better,” Dr. Tadwalkar added. “And that’s really the whole basis behind this is using this nanogel-based drug delivery to target the liver with thyromimetic because this would actually be groundbreaking if it potentially works.”

”Even though the results are compelling, the transition from these preclinical studies to human clinical trials is a big process, as we know, so it’s still very early and we need to see a number of steps come together,” he cautioned.

The liver is the largest solid organ in the body. It is located in the upper right area of the abdominal area, underneath the diaphragm, and on top of the stomach and intestines.

The liver is also quite the overachiever as it performs over 500 different functions the body needs to stay healthy.

These functions include:

There are a number of diseases that can negatively affect the liver, causing potential repercussions for the rest of the body. One of these is fatty liver disease, which occurs in conjunction with obesity.

A study published in September 2022 found that high cholesterol can not only make fatty liver disease worse but can lead to longer-term liver scarring and immune cell dysfunction.

High cholesterol can also cause inflammation of the liver, increasing the risk for other liver diseases and damage.

Conversely, an inflamed liver may reduce the production of bile, resulting in high cholesterol levels in the body.

MNT also spoke with Dr. Mir Ali, bariatric surgeon, and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, CA, about the recently published study.

Dr. Ali agreed with Dr. Tadwalkar that further testing is necessary, as not everything in animal models translates to humans.

However, he also said he found the research interesting, as it shows how obesity affects every organ, and that there is a lot more we need to learn about obesity.

“It’s interesting that something you can block in the liver can affect your weight — it’s not something somebody normally thinks of when they think of obesity,” he added.

When it comes to keeping your liver healthy, Dr. Ali said when people develop obesity, they end up with a fatty liver and that can lead to long-term damage to the liver.

“So any kind of weight loss, maintaining a healthy weight, will help reverse those damages,” he continued.

“On top of that, if you already are prone to a fatty liver, you want to avoid other toxins in the liver. Particularly alcohol is quite toxic to the liver, so the more you avoid alcohol the healthier your liver can be,” Dr. Ali advised.