A Grapefruit Diet, But For Your Cells

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With obesity and type 2 diabetes on the rise in America, understanding the way the body processes fats and sugars is becoming increasingly important. Fortunately, in the past few decades, researchers have made much progress in elucidating the cellular pathways relevant to lipid and carbohydrate metabolism, unraveling the actions of the molecular players involved.

Through this research, a handful of nuclear receptors — proteins inside cells that are responsible for responding to certain chemical signals by modulating the transcription of genes into new RNA and eventually new proteins — have been found to be particularly important in defining how the body keeps lipid and carbohydrate levels in check. The peroxisome proliferator-activated receptors (PPARs) are a set of nuclear receptors that regulate genes crucial for the breakdown and storage of lipids. PPAR comes in a number of forms that have similar functions, but differ according to what type of cell they are active in and what set of genes they directly regulate: PPAR{alpha} is active in the liver, as well as in muscle, and other tissues; PPAR{beta}/{delta} appears throughout many tissue types all over the body; and PPAR{gama} is mainly associated with adipose tissue (fat).

Another nuclear receptor important to lipid and carbohydrate homeostasis, the Liver X Receptor (LXR), works in concert with the PPARs to maintain balance within the body. Like PPAR, LXR comes in several forms, including LXR{alpha}, which is found in many tissues but is most abundant in the liver, and LXR{beta}, which is found all across the tissues of the body. In contrast to PPAR that controls the breakdown of lipids during fasting, LXR is usually up regulated after a meal inducing the synthesis of triglycerides and cholesterol.

Each of these nuclear receptors is a key component of lipid and carbohydrate metabolism, and thus they have been the focus of many pharmaceutical approaches to alleviating the burden of obesity on the body. Drugs that target PPAR, for example, have proven effective at lowering cholesterol levels, reducing insulin resistance, and even preventing atherosclerosis (hardening of the arteries).

Despite the success of many of the drugs targeting these receptors, though, they are not without risks. Rosiglitazone, for example, targets PPAR{gama}, and has successfully been used by many to reduce insulin resistance and improve vascular health. However, rosiglitazone, marketed under the brand name Avandia, has recently come under much criticism for potentially increasing the risk of heart failure.

Nonetheless, given the potential benefits of targeting these nuclear receptors, important as they are to alleviating some of the detrimental effects of metabolic disorders, the industry is not ready to give up on therapies based on activating PPAR and its related receptors. Any possibility of targeting PPAR and LXR without damaging side effects would be very promising– and so I was quite interested to hear that a group of researchers spread across Massachusetts and Jerusalem had found that a common and completely natural molecule could activate PPAR and LXR.

This molecule, called naringenin, belongs to a family of compounds abundant in citrus fruits called flavonoids, and is perhaps best known as the reason grapefruits are bitter. Could a fruit really have beneficial effects on lipid and carbohydrate homeostasis in the body? To find out more, we spoke to Dr. Yaakov Nahmias, the director of the Center for Bioengineering in the Service of Humanity (CBSH) at the Hebrew University of Jerusalem, whose research is focused on the development of new concepts for the treatment of metabolic diseases such as obesity, diabetes, and atherosclerosis.

Is there good reason to believe eating grapefruit can help against diabetes? Do you think people with diabetes should start eating grapefruit?

The answer to both of these questions is a qualified no. Grapefruit and citrus fruit in general contain minerals, fiber, and vitamins, such as vitamin C and folate, which are important for a well-rounded diet. However, these fruits also contain impressive amounts of sugar, about 7.3 grams sugar per 100 grams of grapefruit (32 grams sugar for 1 pound grapefruit) and therefore should be eaten sparingly, especially by people with diabetes.

Dr. Nahmias in his lab

It is also important to mention that eating grapefruit could dangerously increase the concentrations of drugs such as cholesterol-lowering lovastatin, as well as immunosuppressants such as cyclosporine. This is due to the presence of flavonoids, such as naringenin and furanocoumarins in grapefruit, which inhibit CYP3A4, an enzyme responsible for breaking down drugs in our digestive tract. Potential grapefruit effects are usually marked on the package insert of your prescription medication.

The good news is that our work found that naringenin, the flavonoid responsible for the bitter taste in grapefruit, could have a strong insulin sensitizing and lipid lowering effect. Regretfully, naringenin is not absorbed well by our digestive track. Patients would need to consume 40 grapefruits a day to get a therapeutic effect. This is obviously not a good idea considering the amount of sugar in the fruit.

Could naringenin be taken in supplement form?

Our work is very preliminary, and will need to go through several rounds of clinical trials before we can recommend it to patients. Although naringenin is available over the counter in a supplement form, I would urge everyone to use caution and consult their physician before they take any form of dietary supplement, including naringenin.

We do envision – somewhere down the line – that patients will take naringenin as a dietary supplement following a physician consultation. As the compound effects estrogen metabolism, it should definitely be avoided by women who have a risk of breast cancer and those who are pregnant. A patient would need to consume 3-4 grams of naringenin several times a day to see a therapeutic effect.

That said, my lab at the Hebrew University of Jerusalem is currently working on a formulation of naringenin, which is readily absorbed and can be easily taken as a single capsule. We hope to publish later this year.

You show that naringenin may help to normalize hepatic lipid profiles. How would this translate to anti-diabetic effects like insulin-sensitization or regulation of glucose-release?

You might be referring to another paper published earlier this year. What we show is that naringenin inhibits triglyceride and bile acid production, while increasing ketone bodies formation in the liver. These are the hallmarks of a fasted state, supported by gene expression and transcriptional activity data. This fasted state, and PPAR{alpha} induction do make the liver more sensitive to insulin, but the liver is a minor player in glucose clearance. More importantly, naringenin also induces PPAR in other cells like peripheral fat and muscle, which become more insulin sensitive.

The important point is that in contrast to other drugs, such as fenofibrate and lovastatin, which target only a single pathway in the liver, naringenin appears to target all of them by inducing a fasting-like state. This is caused by the simultaneous up regulation of PPAR{alpha} and down regulation of LXR{alpha}. The liver begins to breakdown triglycerides and stops cholesterol synthesis, even when glucose levels are high. We believe that this well-rounded response will have fewer side effects than each of these lipid-normalizing drugs alone.

You cite evidence of the benefits of naringenin as an anti-inflammatory agent, an anti-carcinogenic agent, and as a modulator of hypolipidemia (high cholesterol); is there any evidence– molecular, epidemiological, or otherwise– that directly demonstrates any anti-diabetic effects of naringenin?

There are some, for example:

http://www.ncbi.nlm.nih.gov/pubmed/19727895

http://www.ncbi.nlm.nih.gov/pubmed/19592617

However, I would not trust much of the work on this topic as naringenin absorption through the gut is below 6% and its half-life is about 2.3 hours. Most of these studies use naringenin at concentrations far below its effective dose. The problem with taking a small amount of the compound, even for a prolonged period of time, is that nuclear receptors often display a switch-like response. If you are below the effective dose, you won?t see a response. Our next paper is in review and deals with drug-delivery.

Has all of your analysis thus far been in vitro? Do you plan any in vivo studies to evaluate the action of naringenin?

We have a clinical trial running right now in Massachusetts General Hospital on the application of naringenin in the treatment of HCV infection. We’ve studied three patients so far and are still recruiting.

Have you done any analysis of the other citrus flavonoids? Do those also exploit nuclear receptor pathways?

Yes, it is a common pathway. We have a review on the way.

Despite the benefits seen with PPAR agonists, there is a growing amount of concern about the risks and side effects like weight gain, fluid retention, coronary damage, and bone fracture. Rosiglitazone (sold as GSK’s Avandia) recently became the poster child for PPAR-ligand risks, but it is not the only ligand that has raised questions; for example, Bristol Myers-Squibb’s dual PPAR{alpha} and PPAR{gama} agonist, Muraglitazar, was killed by the FDA after Phase III trials due to concerns about cardiovascular risks. Has there been any analysis of naringenin’s side effects and risks in light of the general concerns about PPAR ligands?

There are decades of experience with naringenin in low doses and several clinical trials, which showed no elevation of risk. It certainly helps when the drug is a dietary supplement, but long-term effects of high doses of naringenin are yet unexplored. Naringenin has a very different structure from Muraglitazar, and its half-life is much shorter. We are aiming at giving it just prior to a meal to keep its circulating level minimal. We do believe it is important to coordinate a well-rounded response, by targeting multiple pathways, like PPAR and LXR, rather than hit a single pathway, which may throw metabolism off balance.

 

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