Transcript
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Hannah Berner (1:43)
Hi, this is Hannah Berner, co host of Giggly Squad. Let's be honest, we've all done things in our lives that may have just followed the crowd, like drinking matcha, even if you think it tastes like grass or pretending skinny jeans were actually comfortable. Have we been doing the same thing with Zero Sugar Cola? Last year, people across America took the Pepsi Challenge. No labels, no bias. Judged on taste alone, 66% of participants agreed. Pepsi Zero sugar tastes better than Coke Zero sugar and Pepsi Zero sugar won in every single market. Go out and try Pepsi Zero Sugar today. You deserve taste. You deserve Pepsi.
Ben Bickman (2:26)
Welcome to the Metabolic Classroom Podcast. I'm Hello, I'm Ben Bickman. Thanks for letting me be your guest professor for the next few minutes. Don't worry about any pop quizzes. I'm here to simply make the science of metabolism clear, practical and engaging. Welcome back to the Metabolic Classroom. I'm Ben Bickman, metabolic scientist and professor of cell biology. Today's mini lecture aims to teach you about something you probably haven't thought much about. That is bile. If you've studied any biology, you likely think of bile as a yellowish fluid that helps you digest fat. And that's not wrong. You'd be right. That's certainly one of its jobs. But bile acids, the active components within bile, are now recognized as bonafide hormones. They are signaling molecules that talk to tissues throughout the body, influencing insulin sensitivity, mitochondrial function, thyroid hormone activation, fat cell behavior, and even inflammation. Today, we'll start with the basics. What bile is, where it comes from, and what it does in the gut. Then we're going to follow bile on a journey most people will never hear about, back into the blood, and from there into tissues where they exert remarkable metabolic effects. We'll also talk about what happens when people lose their gallbladder and whether bile acid supplements actually do anything useful. All right, let's start with just the basics on bile. Well, it's a fluid produced by the liver cells, the hepatocytes, that's the main cell type within the liver. An adult liver produces somewhere in the range of 400 to 800 milliliters of bile per day. It's roughly 95% water. But dissolved in that water are several key components. The most metabolically important of these components are the bile acids, sometimes called bile salts. These are synthesized from cholesterol. And I want to note that because bile acid synthesis is actually the primary route through which the body eliminates cholesterol, that cholesterol is then dumped out. So when you think about cholesterol being made in the body, and what is something that takes out cholesterol? Well, it's actually because the cholesterol gets diverted into becoming bile. Now, of course, beyond bile acids, bile also contains phospholipids, so a different type of fat, some straight cholesterol, and even bilirubin, which gives bile its characteristic color, that yellowish, slightly greenish color. The two primary bile acids produced by the human liver are cholic acid and chinodeoxycholic acid. Before secretion, these are conjugated, so they're bound up with either the amino acid, glycine, or taurine, making them more water soluble and more effective in the gut. So it just allows the bile to just work a little better. Once it's formed, bile is secreted into tiny channels called bile canaliculi. These are pathways, like almost vessels, which then merge into larger bile ducts. From there, biological bile either flows directly into the duodenum, the early part of the small intestine, or it's diverted into the gallbladder for storage. In the gallbladder, the bile is concentrated roughly five to ten fold. When you eat a meal containing fat, a hormone called cholecystokinin or CCK signals the gallbladder to contract and release all of that concentrated bile into the intestine. Once it's in the gut, the bile acids will emulsify dietary fats. That's its most famous role. It acts as a biological detergent, breaking up the large fat globules into very tiny little droplets called me cells, which of course then dramatically increases the surface area of all the fat, which allows the liver or the fat breakdown enzymes, the lipases, to do their work. The lipases are that family of enzymes that are designed to digest or help the body break down fat. Without bile, it's no surprise fat digestion is going to be severely impaired and you'll lose some of the ability to properly absorb not only fat, but also some fat soluble vitamins like those being A, D, E and K. Now the story starts to get really interesting as we continue through the after the production of bile, bile acids don't just do their job in the gut and then disappear, roughly 95% of bile acids secreted into the intestine are reabsorbed primarily in the what's called the ileum. So the back part of, in fact the back part of the back part of the small intestine. Once absorbed, they enter the portal blood, which means that's going from the gut straight to the liver and are re secreted into bile. This recycling loop is called the enterohepatic circulation. We're going to come back to that later. And it is remarkably efficient. The total bile acid pool is only about 2 to 4 grams, but it cycles 6 to 12 times per day. Only about 5% is lost in feces daily, replaced then by synthesizing new bile from cholesterol. The key insight that has transformed bile acid biology is this. When bile acids are reabsorbed into the blood, they don't just quietly return to the liver. They interact with specific receptors, nuclear receptors inside the cells, as well as membrane bound receptors on the surface of the cells. And it does so in the gut and in the liver and tissues throughout the body. It's through these receptors that bile acids exert their metabolic effects. And now of course, I get to then as a metabolic scientist, talk about a topic that is always dear to my heart. And let's focus on the two most important metabolic effects when it comes to bile acids. The first is fxr, the farnesoid X receptor. This is a nuclear receptor, so it's found within the nucleus. Identified as a bile acid receptor in 1999, this finding established that bile acids could directly react regulate gene expression. FXR is most active in the liver and intestine, and the metabolic effects of its activation are substantial. In the liver, FXR tells the cell to dial down lipogenesis, the machinery that builds new fat molecules. The net effect is less fat accumulation in the liver. And as we've discussed previously on the podcast, a fatty liver is one of the most potent drivers of insulin resistance. It actually ends up being both cause and consequence of insulin resistance. And FXR activation also improves hepatic insulin signaling. It promotes glycogen synthesis and reduces the liver's tendency to overproduce glucose. That's of course one of the key problems as a person transitions from insulin resistance to outright type 2 diabetes. It's that the liver begins misbehaving and overproducing glucose. Well, bile acids help solve that problem. In the intestine, FXR triggers production of FGF19, that stands for fibroblast growth factor 19. This hormone travels to the liver and delivers a clear metabolic message. Stop making so much glucose and stop making so much bile acid. So it ends up being a bit of a negative feedback. A 2011 paper in Cell Metabolism found that FGF19 inhibits the liver's the liver's glucose production pathway. Exactly what you want in someone struggling with high blood glucose, like in type 2 diabetes. Think of it this way. Every time bile acids are reabsorbed and activate fxr, it's like a metabolic reset of sorts. The liver starts to reduce its fat production. It reduces its glucose output and improves its insulin sensitivity. The built in metabolic housekeeping is a result of this, and it's triggered by something that is produced when you've eaten your last fatty meal.