The concept of “good fats” and “bad fats” has influenced diet trends, public health policy and biomedical research for decades. Now, a new study led by Thomas A. Vallim, PhD, a researcher and professor of medicine in the UCLA Division of Cardiology, offers new insights into how the body handles “good fats” and “bad fats” at the molecular level — opening a door to new treatments for obesity, diabetes and other metabolic conditions. Their study¹ is featured on the cover of the February edition of Cell Metabolism.

“We found that if you can tweak bile acids, you can find a way to selectively absorb the good fats and excrete the bad fats, with many metabolic benefits,” Dr. Vallim said. That includes the secretion of hormones like glucagon-like peptide-1 (GLP-1), the same mechanism that underlies popular weight loss drugs like Wegovy and Ozempic.  

Dietary fat is essential to survival, and humans have evolved to process it very efficiently. Bile acids are detergent molecules that help break fat into small droplets in the intestine, allowing fats to be efficiently absorbed into systemic circulation. While this was quite useful for our ancestors living in times when food was scarce, this advantage becomes a disadvantage in a world where high-fat food options are readily available. The typical Western diet is high in fat, especially saturated fat — which is associated with inflammation and often implicated in metabolic disease. Other types of fat, monounsaturated and polyunsaturated fats, are known to protect the heart and liver but found less frequently in a Western-style diet. This study, led by co-first authors Alvin P. Chan, MD, PhD; Kelsey E. Jarrett, PhD; and Rochelle W. Lai, MS, RD, CSP, set out to better understand how bile acids regulate lipid absorption in metabolic disease. 

Dr. Jarrett, an assistant project scientist in the Division of Cardiology, engineered a CRISPR tool to disable a critical enzyme for bile acid synthesis, CYP7A1. The tool successfully decreased bile acid levels by 50% in adult mice.    

"I used some of the same delivery techniques that are being used for human gene therapies, but with the purpose of understanding new things about biology and nutrition,” Dr. Jarrett said. “Our first goal here was to decrease bile acid levels to see if fat absorption decreased. To do that I used gene editing in adult mouse liver to make an important bile acid gene nonfunctional." 

While decreasing bile acids for the sake of decreasing fat absorption made sense, Lai, a dietitian who is working towards a doctorate in the UCLA Molecular, Cellular and Integrative Physiology program, questioned whether blocking fat absorption was truly novel. She suggested a second group of mice receive orlistat, an FDA‑approved weight‑loss drug (marketed as Alli) that blocks fat absorption in a mechanism distinct from decreasing bile acids to serve as a positive control. For eight weeks, each group of mice was fed a high-fat diet that mimics a Western diet — think greasy cheeseburger, fries, and a sugary soda. Although both groups absorbed less fat, only the mice lacking CYP7A1 were protected from weight gain. 

While the Cyp7a1 CRISPR mice ate the same amount as their controls, the orlistat group ate more. To see how the two approaches influenced absorption, the researchers then used oxygen bomb calorimetry to analyze the caloric, or energy, content of animals’ fecal matter. Both the Cyp7a1 CRISPR mice and the orlistat-treated mice excreted more calories in their feces, but only the Cyp7a1 CRISPR mice did so without a compensatory increase in appetite.  

The team was surprised that the mice without the CYP7A1 enzyme did not eat more and wondered if this mechanism could be leveraged to reduce obesity. To explore this further, they measured circulating levels of satiety-related hormones and found that GLP-1 secretion was markedly greater in the mice without CYP7A1 than in those on orlistat. After additional analyses suggested that GLP-1 release was being driven by fat absorption, the researchers examined where in the intestine the fat was being absorbed. Unlike control mice, Cyp7a1 CRISPR mice absorbed fat further down the digestive tract than normal. 

“We think what’s happening is that as these fats travel further into the gut, they stimulate some receptors that promote the secretion of GLP-1,” Dr. Vallim explained. “That’s a way that your body tells your brain, ‘Hey, I’ve had enough of this nutrient.’”  

After establishing the link between bile acids, appetite, and fat absorption, the researchers investigated how altered fat absorption reshapes fat metabolism in the liver — the central hub for fat distribution — and other tissues. Through a combination of lipidomic analysis, histological examination and other techniques, they found that both bile acid reduction and orlistat treatment change what types of fatty acids end up in tissues, but to opposite metabolic ends. In Cyp7a1 CRISPR mice, the liver shifted toward higher levels of polyunsaturated “good” fats and lower levels of saturated “bad” fats. In contrast, orlistat broadly reduced fat absorption, including beneficial polyunsaturated fats. As a result, orlistat-treated mice activated liver pathways that generate new fats, a response that promotes metabolic dysfunction over time. 

Next, the team asked whether changes in liver fat were driven by how different fats were absorbed, rather than by the mice simply eating less fat overall. By tracking the absorption of individual fatty acids, they found that Cyp7a1 CRISPR mice continued to absorb polyunsaturated “good” fats while allowing more saturated “bad” fats to pass into the stool—a pattern that matched what they saw in the tissues. 

Given their findings so far, Dr. Vallim’s team then set out to elucidate the mechanism by which bile acids were changing fat absorption. As detergent molecules, bile acids transport fatty acids by wrapping them up in particles called micelles. The researchers hypothesized that some fats might simply be easier to put into micelles than others. 

To test this idea, they took bile from mouse gallbladders and mixed it with individual fatty acids. The results validated what they had seen so far: Saturated fats took relatively large amounts bile to dissolve, while unsaturated fatty acids required much less. The researchers then tested the same idea out with human bile, which has different bile acid composition. Using bile from an otherwise healthy patient following the removal of the gallbladder, they demonstrated that the mechanism was the same across species — saturated fatty acids required more bile to break down than unsaturated fatty acids, meaning that they were less readily absorbed. It was noteworthy that much less human bile was necessary to break down fatty acids compared to mice, suggesting that humans absorb fat more easily. 

Dr. Vallim’s team next set out to understand how individual bile acids contribute to fat absorption. To do so, they used CRISPR  targeting different enzymes involved in bile acid synthesis in a way that made the combination of bile acids similar to that of humans. After seeing the results, they then added different bile acids back in one at a time to see how they influenced fat absorption. The results showed that not all bile acids move fat equally. When the researchers removed an enzyme for the formation of a specific bile acid, called cholic acid, saturated fat absorption was reduced, while unsaturated fats continued to be absorbed almost normally. Adding back the CA in diet confirmed its key role in saturated fat absorption.  

Prior to this study, conventional wisdom held that all fat is absorbed in the same way through a largely passive, non-specific process. The team’s results show that fat absorption is far more selective than previously thought. 

“We show that this is due to bile acids and that by manipulating bile acids, you can manipulate absorption,” Dr. Chan, a pediatric gastroenterologist and recent graduate from the UCLA STAR program, explained.  

Just as they found that all fats are not absorbed in the same way, the researchers also showed that not all bile acids are created equal.  

“We often think of bile acids as a group of molecules, not that they each have their own specific physiochemical functions,” Lai said. “Seeing bile acids and absorption as multi-faceted molecules and processes adds novelty to our paper that previous research might not have put together.”  

The team is now collaborating with other UCLA faculty to design small molecules that can target the bile acid-fat absorption pathway therapeutically to improve metabolic health.  

“We think there is a lot of potential in targeting this system and maybe specific bile acids,” Dr. Vallim said. “We’re interested in pursuing all those avenues and, potentially, in developing new therapies.” 

Reference:

1) https://www.cell.com/cell-metabolism/fulltext/S1550-4131(25)00494-2

(Newswise/HG)