I am a huge fan of Italian bitter liqueurs. I was first introduced to the idea when I was working at Memorial Sloan-Kettering in Manhattan. A co-worker brought in a six pack of bitter soda from a local pizza place. I took a sip. It was revolting. My only thought was, “this tastes like bile! Literally dry heaves.”
It was weird, though, the sweet and tart balanced out the bitter somehow. I took another sip. Still very odd, but somehow I enjoyed it?
Fast forward 20 years and I have developed a love of Italian Amaro. The most well known (in the US) of which is Campari. I delight in initiating new members of the Campari club. The conversation goes something like this.
“Have you ever had Campari?”
“No. What is it?”
“It’s an Italian bitter liqueur. It tastes like bile.”
“Yeah, literally like dry heaves but sweet and nice somehow.”
Somehow I usually get them to try it. Most people drink Campari in a cocktail such as a negroni but I just drink it straight at room temperature. Reactions to it… vary.
A Medicinal Liqueur
Italians have been making Amaro since Greek and Roman times. A legend is that Pliny the elder, who died in 79 AD, made amari. After that, monks took up the tradition of making regional Amari. Amari is the plural.
Since the beginning, Amaro has been considered a health drink. It is made from grape brandy with a neutral flavor that is steeped with botanicals which can include gentian root, citrus peel, wormwood, rhubarb root, aloe, mugwort, cinnamon, and hundreds of others.
European alchemists remain persuaded that elixirs had beneficial qualities and, in particular, could prolong life—a belief they shared, or perhaps imported from Chinese culture.“Amari” , Carla Passino, Italy Magazine.
Hundreds of years ago, our ancestors sipped liqueurs to strengthen their constitution. “They thought multiple sips a day kept any ailments away,” says Vance Henderson, brand ambassador for Drambuie. … According to legend, Henry IV, the king at that time in 1605, sent a representative to their monastery in Vauvert to deliver the directions for making the “elixir of long life.”“The Medicinal Roots of Modern Liqueurs”, Meredith Bethune, Mar 22, 2017
Bitter Amari are often taken before a meal as an aperitif or after a meal as a digestif. This is said to stimulate bile production and aid in digestion.
Bile Acid Receptors and AMPK
The monks may have been onto something. In recent posts I’ve talked about the molecular sequence of events leading from consumption of linoleic acid to a torpid metabolism and that the best way to escape the torpid metabolism might be to stimulate AMPK.
There are two bile acid receptors, known as tgr5 and FXR.
Tgr5 is expressed on the cell surface and when it is activated by certain specific bile acids, it activates adenylate cyclase which creates cAMP, which activates AMPK1. Tgr5 is expressed in most tissues, including liver, the small and large intestine, the brain and the adrenal glands.
Tgr5 also causes GLP-1 to be released into the bloodstream. GLP-1 is a circulating hormone that … wait for it … activates AMPK2.
FXR is yet another member of the nuclear receptor superfamily, just like PPARy and the aryl hydrocarbon receptor (AhR). In a recent article I explained that members of the “superfamily” are transcription factors (they turn other genes on) that form dimers (they bind to another family member) before they can do their job. It takes two to tango.
SREBP-1c and LXR are members of the superfamily who form a dimer to increase the expression of lipogenic (fat making) genes. AMPK phosphorylates SREBP-1c and turns it off.
When FXR is activated it increases the expression of SHP3, which binds to LXR and blocks it. Without a binding partner, SREBP-1c can’t increase the expression of lipogenic genes, including SCD1. Low levels of SCD1 increase activation of AMPK.
So the bile acid receptors are coordinating to increase AMPK activation. Tgr5 is increasing the activity of AMPK directly, but also indirectly via the release of GLP-1. AMPK and FXR are coordinating to turn off lipogenic gene expression, including SCD1, both through AMPK phosphorylation of SREBP-1c and by FXR increasing expression of SHP, which competes with SREBP-1c for LXR. Low levels of SCD1 increase activation of AMPK.
Campari tastes like bile
The reason that the Amari have a bitter taste, like bile, is that the body sees the bitter polyphenols as bile.
Gentian is known as the king of bitter herbs and it is the most common bittering agent in Amari. The bitterness of gentian is caused by a polyphenol called gentiopicroside. Gentiopicroside is a tgr5 agonist (turns it on)4. Gentiopicroside has been shown to prevent obesity in a diet induced obese rodent model.5
The second major component of Amari is citrus.
Without citrus to relieve the tension between bitter and sweet an amaro just doesn’t have all the notes it needs.“The 14 Most Popular Herbs and Botanicals in Amaro, Explained”, Louis Catizone, Vinepair.
Citrus polyphenols are FXR agonists (turns it on)6. A gut specific FXR agonist was shown to prevent obesity in a rodent model7.
So combining gentian and citrus will activate both bile acid receptors.
A dual bile acid receptor agonist has been shown to prevent Progression of Nephropathy in Diabetes and Obesity.8
Solubility of polyphenols
Bile acids are made by oxidizing cholesterol. Cholesterol is a polycyclic hydrocarbon that is fat soluble. Adding oxygen to this structure makes most bile acids somewhat soluble in water. The same is true of polyphenols. They are slightly soluble in water. This property of being sorta fat soluble, sorta water soluble gives them a detergent property that helps us digest.
An issue with polyphenols is that they are not well absorbed. If you can get them solubilized, they are more likely to be absorbed. Another thing that’s sorta fat soluble, sorta water soluble is ethanol. Polyphenols are more soluble in ethanol than they are in water.9
The monks knew what they were doing.
Readers of this blog know that I love it when traditional food pathways converge with modern science. Pliny the elder knew that bitter herbs were good for us. He may have learned that from the Chinese. If you do a google scholar search for “gentiopicroside tgr5” all of the hits are from 2020 and 2021. The literature about citrus polyphenols and FXR go back as far as 2016. We are just figuring out WHY polyphenols are good now.
For a long time it has been thought that polyphenols were “good”. They have been described as antioxidants and hormetic agents. I like root causes, though. Perhaps the main mechanism of polyphenols is triggering bile acid receptors, which upregulate AMPK, which upregulates PPARa, which upregulates mitochondrial uncoupling. Uncoupling proteins are fantastic anti-oxidants. Perhaps polyphenols are simply “plant bile acids”.
You can of course get citrus polyphenols as supplements. Citrus polyphenols probably stimulate tgr5 as well as FXR10. But the next time it’s cocktail hour, consider that negroni. Amaro is also great added to seltzer over ice. I’ll also leave you with my Camparita recipe.
- 1 Oz Tequila Blanco
- 1 Oz Campari
- 1 Oz Fresh squeezed lime juice
- 1 pinch Salt Salt to taste or salt the rim
- Pour all ingredients over ice. Salt to taste.
Update: Stappj is a non-alcohol Italian Bitter Seltzer
For those who don’t want alcohol. I can’t vouch for it personally. Also, Raphael added a pathway drawing.
- 1.Keitel V, Gertzen CGW, Schäfer S, et al. Bile Acids and TGR5 (Gpbar1) Signaling. In: Mammalian Sterols. Springer International Publishing; 2020:81-100. doi:10.1007/978-3-030-39684-8_4
- 2.He Q, Sha S, Sun L, Zhang J, Dong M. GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway. Biochemical and Biophysical Research Communications. Published online August 2016:196-203. doi:10.1016/j.bbrc.2016.05.086
- 3.Watanabe M, Houten SM, Wang L, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest. Published online May 15, 2004:1408-1418. doi:10.1172/jci21025
- 4.Xiao H, Sun X, Liu R, et al. Gentiopicroside activates the bile acid receptor Gpbar1 (TGR5) to repress NF-kappaB pathway and ameliorate diabetic nephropathy. Pharmacological Research. Published online January 2020:104559. doi:10.1016/j.phrs.2019.104559
- 5.Choi R-Y, Nam S-J, Lee H-I, et al. Gentiopicroside isolated from Gentiana scabra Bge. inhibits adipogenesis in 3T3-L1 cells and reduces body weight in diet-induced obese mice. Bioorganic & Medicinal Chemistry Letters. Published online July 2019:1699-1704. doi:10.1016/j.bmcl.2019.05.038
- 6.Liu L, Liu Z, Li H, et al. Naturally Occurring TPE-CA Maintains Gut Microbiota and Bile Acids Homeostasis via FXR Signaling Modulation of the Liver–Gut Axis. Front Pharmacol. Published online February 6, 2020. doi:10.3389/fphar.2020.00012
- 7.Fang S, Suh JM, Reilly SM, et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. Published online January 5, 2015:159-165. doi:10.1038/nm.3760
- 8.Wang XX, Wang D, Luo Y, et al. FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity. JASN. Published online October 31, 2017:118-137. doi:10.1681/asn.2017020222
- 9.Ariño A, Arberas I, Leiton MJ, de Renobales M, Dominguez JB. The extraction of yellow gentian root (Gentiana lutea L .). Zeitschrift f�r Lebensmitteluntersuchung und -Forschung A. Published online September 26, 1997:295-299. doi:10.1007/s002170050168
- 10.Yang Y, Tian A, Wu Z, Wei Y, Hu X, Guo J. Finger Citron Extract Ameliorates Glycolipid Metabolism and Inflammation by Regulating GLP-1 Secretion via TGR5 Receptors in Obese Rats. Uzor PF, ed. Evidence-Based Complementary and Alternative Medicine. Published online March 27, 2021:1-11. doi:10.1155/2021/6623379