International Journal of Molecular Sciences Review Cafestol and Kahweol: A Review on Their Bioactivities and Pharmacological Properties Yaqi Ren 1, Chunlan Wang 2, Jiakun Xu 2,* and Shuaiyu Wang 1,* 1 College of Veterinary Medicine, China Agricultural University, Beijing 100193, China 2 Key Laboratory of Sustainable Development of Polar Fisheries, Ministry of Agriculture and Rural Affairs, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences; Laboratory for Marine Drugs and Byproducts of Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266071, China * Correspondence: [email protected] (J.X.); [email protected] (S.W.); Tel.: +86-138-6982-8530 (J.X.); +86-136-1100-7081 (S.W.) Received: 17 July 2019; Accepted: 18 August 2019; Published: 30 August 2019 Abstract: Cafestol and kahweol are natural diterpenes extracted from coffee beans. In addition to the effect of raising serum lipid, in vitro and in vivo experimental results have revealed that the two diterpenes demonstrate multiple potential pharmacological actions such as anti-inflammation, hepatoprotective, anti-cancer, anti-diabetic, and anti-osteoclastogenesis activities. The most relevant mechanisms involved are down-regulating inflammation mediators, increasing glutathione (GSH), inducing apoptosis of tumor cells and anti-angiogenesis. Cafestol and kahweol show similar biological activities but not exactly the same, which might due to the presence of one conjugated double bond on the furan ring of the latter. This review aims to summarize the pharmacological properties and the underlying mechanisms of cafestol-type diterpenoids, which show their potential as functional food and multi-target alternative medicine. Keywords: cafestol; kahweol; serum lipid; anti-inflammation; anti-tumor; anti-diabetes 1. Introduction Coffee is one of the most wildly consumed beverages in the world. Extensive experiments and meta-analysis of studies show that coffee consumption is associated with the risk of some human diseases [1]. Statistics show that moderate consumption of coffee (3 to 5 cups/day) reduces the risk of cardiovascular disease [2]. There is growing evidence that coffee can prevent some chronic diseases such as cancer, cardiovascular disease, metabolic disease, and cirrhosis [1–5]. The main active compounds in coffee that play these roles include caffeine, chlorogenic acid, cafestol and kahweol [6,7]. Cafestol and kahweol are natural diterpenes extracted from coffee beans, which mainly present as fatty esters in unfiltered coffee like Turkish coffee [8]. Unfiltered coffee contains 3–6 mg of these diterpenes per cup [9]. The only difference of their structures is that kahweol has an extra double bond [10] (Figure1). In vivo, About 70% of the consumption of cafestol and kahweol can be absorbed in small intestine [11]. In theory, glucuronidation and sulphation are the major pathways of xenobiotic biotransformation in mammalian species, which occurs largely in the liver, to produce water-soluble products that can be excreted by urine [11]. However, only about 1% or less of the consumption was detected to be excreted as conjugate of glucuronic or sulphuric acid in urine in previous studies [11,12]. It indicates that the major part of the absorbed cafestol and kahweol must be subject to more extensive metabolism, not just by glucuronidation or sulphation. There is evidence that cafestol and/or its metabolites largely accumulate in liver and gastrointestinal tract through the enterohepatic cycle [13]; triggering a variety of biological effects, including secondary changes in liver metabolism. Int. J. Mol. Sci. 2019, 20, 4238; doi:10.3390/ijms20174238 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 4238 2 of 15 Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 14 1 Early studies confirmedconfirmed that cocoffeeffee diterpenesditerpenes (especially(especially cafestol), eeffectivelyffectively increase humanhuman 2 plasma triacylglycerol and low-density lipoprotein (LDL), may be a potential risk of inducing some 3 cardiovascular diseasesdiseases [7 ,[7,14].14]. However, However, from from a more a more comprehensive comprehensive perspective, perspective, cafestol andcafestol kahweol and 4 showkahweol a remarkable show a remarkable two-faced etwo-facedffect. In addition effect. toIn theaddition deleterious to the eff deleteriousects on serum effects lipid on levels serum and lipid liver 5 enzymeslevels and in someliver enzymes cases, extensive in some studies cases, have extens demonstratedive studies that have cafestol demonstrated and kahweol that exhibit cafestol awide and 6 varietykahweol of pharmacologicalexhibit a wide variety activities, of includingpharmacological anti-inflammatory,anti-angiogenic activities, including anti-inflammatory, and anti-tumorigenic anti- 7 properties.angiogenic Withand multipleanti-tumorigenic bioactivities properties. of cafestol With and multiple kahweol reported,bioactivities the of development cafestol and of potentialkahweol 8 multi-targetreported, the drugs development with diterpenes of potential should multi-target be encouraged. drugs with Therefore, diterpenes it is ofshould great be significance encouraged. to 9 summarizeTherefore, it the is pharmacologicalof great significance and to biological summarize studies the onpharmacological the two compounds, and biological review the studies mechanisms on the 10 behindtwo compounds, the effects, review and get the a comprehensivemechanisms behind picture the of effects, their miscellaneousand get a comprehensive functions. picture of their 11 miscellaneous functions. 12 13 Figure 1.1. Structure and chemicalchemical characteristicscharacteristics of cafestolcafestol andand kaweol.kaweol. They are naturalnatural diterpenesditerpenes 14 extracted from cocoffeeffee beans.beans. 2. Biological and Pharmacological Activities of Cafestol and Kahweol 15 2. Biological and Pharmacological Activities of Cafestol and Kahweol 2.1. Raising Serum Lipid 16 2.1. Raising Serum Lipid Since Thelle et al. first found a positive correlation between coffee consumption and serum 17 concentrationSince Thelle of total et al. cholesterol first found and a triglycerides positive correlation in 1983, many between studies coffee have consumption supported their and findings serum 18 overconcentration the years [15of ].total It is confirmedcholesterol that and long-term triglyceri consumptiondes in 1983, of many unfiltered studies coff eehave will supported effectively causetheir 19 thefindings increase over of the plasma years triacylglycerol [15]. It is confirmed and low-density that long-term lipoprotein consumption (LDL) cholesterol of unfiltered in humans coffee [will14]. 20 Theeffectively two diterpenoids, cause the increase cafestol of plasma and kahweol, triacylglycerol are mainly and responsiblelow-density forlipoprotein this effect. (LDL) Plasma cholesterol lipids, 21 especiallyin humans LDL [14]. cholesterol, The two diterpenoids, are important cafestol factors in and promoting kahweol, the are occurrence mainly responsible of cardiovascular for this diseases. effect. 22 PlasmaIn humans,lipids, especially cafestol LDL appears cholesterol, to be more are important effective on factors elevating in promoting serum lipid the thanoccurrence kahweol. of 23 Meta-analysescardiovascular ofdiseases. observational researches showed that after daily treatment with 10 mg of cafestol for 24 4 weeks,In humans, serum cholesterol cafestol appears increased to be by more 0.13 mmoleffectiveL 1on, while elevating kahweol serum raised lipid that than by kahweol. 0.02 mmol Meta- L 1. 25 · − − LDLanalyses cholesterol of observational accounts researches for about 80% showed of elevated that after serum daily cholesterol. treatment with Similarly, 10 mg the of samecafestol dose for of 4 26 cafestolweeks, serum is more cholesterol effective than increased kahweol by to0.13 increase mmol∙ serumL-1, while triglyceride kahweol levels. raised In that the by test 0.02 of volunteers,mmol L-1. 27 cafestolLDL cholesterol increased accounts serum triglycerides for about 80% by 86%,of elevated but the serum combination cholesterol. of cafestol Similarly, and kahweol the same increased dose of 28 thecafestol response is more only effective 7% higher than than kahweol that of to cafestol increase alone. serum With triglyceride the long-term levels. intake In the of test coff ofee volunteers, diterpenes, 29 mostcafestol of theincreased rising serum triglycerides willby 86%, subside but the [16 ,combination17]. of cafestol and kahweol increased 30 the responseThe metabolism only 7% of LDLhigher is primarily than that mediated of cafe bystol the alone. LDL receptor With the pathway. long-term LDL receptorsintake of locatedcoffee 31 onditerpenes, the cell membranes most of the are rising involved serum in triglycerides the endocytic will process subside of lipoproteins[16,17]. containing apolipoprotein 32 B andThe apolipoprotein metabolism of E, LDL thereby is primarily inducing mediated LDL cholesterol by the toLDL be eliminatedreceptor pathway. from the LDL bloodstream. receptors 33 Somelocated studies on the indicate cell membranes that the LDLare involved receptor mayin the be endocytic the active process site for of cafestol lipoproteins and kahweol containing on 34 apolipoprotein B and apolipoprotein E, thereby inducing LDL cholesterol to be eliminated from the cholesterol-raising effect. In vitro studies suggested that cafestol elevated plasma LDL-cholesterol 35 bloodstream. Some studies indicate that the LDL receptor