New drugs for metabolic diseases could come from food waste

Cashew nuts are a healthy snack and a source of “good fat,” but the nut shell liquid, which surrounds the cashew nut in the fruit and is usually discarded as a waste product during harvesting, may hold even more health benefits.

Researchers reported in a new study that molecules from lipid-rich cashew nut shell liquid target nuclear receptors, specifically peroxisome proliferator-activated receptors (PPARs), to regulate lipid metabolism and maintain glucose homeostasis. For those who suffer from metabolic diseases such as obesity or diabetes, these molecules may offer new, sustainably-sourced treatment options. 

“The lipids or fats that we eat, while they're important for the nutritional part of our body’s activity, they're also informational,” said Ronald Evans, an expert in nuclear receptors at the Salk Institute who was not involved in the study. 

Certain lipids regulate various metabolic processes in the body such as adipogenesis and lipid metabolism by binding and activating PPARs. PPARs are nuclear receptors that act as transcription factors and can be classified into three family members, PPARα, PPARγ, and PPARδ. They are expressed in different organs and regulate various aspects of metabolism.

Clinicians previously used a class of PPAR-targeting drugs called glitazars to treat metabolic diseases such as hyperlipidemia and hyperglycemia. Another class of drugs, thiazolidinediones, targeted PPARγ to improve insulin sensitivity in patients with type 2 diabetes. However, prolonged use of these drugs caused serious side effects such as heart failure and bone loss, which halted their use and prevented scientists from studying them further. These side effects were largely attributed to the high potency of the drugs for activating PPARγ. 

In an effort to find safer PPAR-targeting molecules, Luiz Romeiro, a medicinal chemist at the University of Brazil, wondered if the lipid-rich liquid discarded from cashew nut shells might contain a valuable therapeutic agent. He enlisted the help of Carolyn Cummins, a researcher studying nuclear receptors at the University of Toronto, to help understand if the waste product from cashew nut shells held a molecule with partial PPAR-targeting that may be developed into a drug with fewer side effects. 

Romeiro and Cummins screened a library of molecules derived from cardanol and anacardic acid, the two main components of cashew nut shell liquid, for their ability to activate human PPAR variants in a human embryonic kidney cell line. They found that these derivatives acted as single, dual, or even pan-PPAR agonists, with many exhibiting either full or partial PPAR-targeting. 

To determine which PPAR isoforms these molecules bind to and to assess their in vivo  activity, Romeiro and Cummins genetically modified zebrafish to express the binding domain of human PPARs. The in vivo  activity and tissue distribution of the nut shell liquid derivatives depended on the chemical groups present on the molecules.  

From these experiments, they identified the compound LDT409, a novel partial pan-PPAR targeting molecule that is potent and has balanced affinity for PPARα and PPARγ and weak binding affinity for PPARδ. The researchers found that LDT409 activated PPARα in the brain, PPARγ in the hindbrain, and did not significantly activate PPARδ anywhere in the zebrafish model. 

To determine how long LDT409 persists in the bloodstream, the researchers monitored its plasma concentration in mice after feeding them flavoured pellets containing the compound. Using liquid chromatography and mass spectrometry, the researchers determined that giving the mice a daily dose of this compound maintained an effective concentration in the bloodstream.

“LDT409 could potentially be a useful therapeutic for metabolic disease, which affects low- and middle-income countries more than the US and Canada, but the fact that it's produced in Brazil and that it could be extracted and formulated there, I think, to me, is great,” said Cummins.

Evans is interested in how LDT409 could be engineered to target specific tissues. “Can you target it to the liver, for example, because that's where you get a lot of fatty liver disease? Or is there a way to target it to the pancreas, which controls a lot of lipid metabolism?” he asked.

Although this study focused on PPAR targeting, Romeiro and Cummins suspect that LDT409, might also activate other receptors. They hope to identify these other targets in follow up studies.

“This first paper is just the start of the iceberg because there is a huge mountain of data that we are studying,” said Romeiro. 

Reference

 Sahin, C. et al. Phenolic Lipids Derived from Cashew Nut Shell Liquid to Treat Metabolic Diseases. J Med Chem  65, 1961–1978 (2022).