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. 2019 Aug 12;28(5):1287–1296. doi: 10.1007/s10068-019-00662-0

Mechanisms of action of coffee bioactive components on lipid metabolism

Renalison Farias-Pereira 1, Cheon-Seok Park 2, Yeonhwa Park 1,2,✉
PMCID: PMC6811484  PMID: 31695927

Abstract

Coffee consumption is associated with reduced risk of metabolic syndrome, obesity and diabetes, which may be related to the effects of coffee and its bioactive components on lipid metabolism. Coffee contains caffeine, a known neuromodulator that acts as an adenosine receptor antagonist, as well as other components, such as chlorogenic acids, trigonelline, cafestol and kahweol. Thus, this review discusses the up-to-date knowledge of mechanisms of action of coffee and its bioactive compounds on lipid metabolism. Although there is evidence that coffee and/or its bioactive compounds regulate transcription factors (e.g. peroxisome proliferator-activated receptors and sterol regulatory element binding proteins) and enzymes (e.g. AMP-activated protein kinase) involved in lipogenesis, lipid uptake, transport, fatty acid β-oxidation and/or lipolysis, needs for the understanding of coffee and its effects on lipid metabolism in humans remain to be answered.

Keywords: Alkaloid, Phenolic acid, Cholesterol, Obesity, Fat

Introduction

Coffee is an ancient drink that is increasingly popular around the world. People who drink coffee are not only attracted to its flavor, but also to its potential health benefits, including lower risk of metabolic syndrome, obesity and diabetes (Farah, 2012; Grosso et al., 2017; Santos and Lima, 2016). As altered lipid metabolism is common to these conditions, the effects of coffee bioactives on lipid metabolism have been suggested as underlying mechanisms of the health benefits of coffee (Grosso et al., 2017; Santos and Lima, 2016). Therefore, this review primarily discusses the current knowledge of coffee and its bioactive components on lipid metabolism.

Coffee composition

The composition of regular coffee varies mostly according to type of beans, roasting and brewing methods (Cruz et al., 2018; Vignoli et al., 2014). The most popular coffee beans are from Coffeea arabica (Arabica) or C. canephora (Robusta) with significant differences in their composition, including caffeine content; e.g. drinks from Robusta beans had higher caffeine levels than Arabica (Vignoli et al., 2014). Roasting coffee beans degrades heat unstable compounds (e.g. phenolic acids and trigonelline) and changes their sensory profile (Farah, 2012). For instance, light or medium roast coffee beans are used to make coffee drinks with more chlorogenic acids (CGA) than dark roast coffee beans (Vignoli et al., 2014). Brewing methods influence the coffee drink composition as well; Turkish-style coffee drink had higher concentrations of diterpenes (cafestol and kahweol) than filtered coffee drink (Rendon et al., 2018). These differences in composition have shown to influence the potential biological properties of coffee (Cruz et al., 2018).

The most common coffee extraction is performed by hot water from beans, but other plant parts or solvents are used to develop other coffee products. Water extraction from the coffee fruit (pulp) or silver skin (bean testa), usually discarded in the regular coffee production, retained some of the coffee bioactive compounds, containing about 1% CGA and 1–3% caffeine (Ameca et al., 2018; Martinez-Saez et al., 2014; Ontawong et al., 2019b). Different solvent extraction methods change the coffee extract composition. Decaffeinated coffee, which has 2–15 mg caffeine per serving, can be produced by organic solvents or supercritical CO2 methods (de Azevedo et al., 2008; Farah, 2012). Ethanol extraction is used to make the commercially available green coffee bean extracts (GCBE), which contain 27–50% CGA and 2–10% caffeine (Choi et al., 2016; Kim et al., 2014; Shimoda et al., 2006). Taken together, coffee processing methods have a great impact on its composition and related biological properties.

Coffee bioactive compounds

Caffeine (Fig. 1), an alkaloid that has a variety of potential biological effects, is found at concentration between 50 and 380 mg/100 mL in regular coffee drink (Farah, 2012; Grosso et al., 2017). Caffeine is an adenosine receptor antagonist, related to its mostly known function as a neuromodulator, that boosts energy expenditure (Harpaz et al., 2017; Wu et al., 2017). Although caffeine has potential beneficial effects against Parkinson’s disease and type-2 diabetes, some need to control caffeine intake due to its effect on increased blood pressure (Grosso et al., 2017).

Fig. 1.

Fig. 1

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Illustrative summary of the overall effects of coffee and its bioactive compounds on lipid metabolism. Molecular structures of chlorogenic acids (phenolic acids) representative: 5-O-caffeoylquinic acid; alkaloids: caffeine and trigonelline; diterpenes: cafestol and kahweol. ↓, decrease;?, inconclusive; ↑, increase

There are different CGA esters in coffee and their concentrations combined range from 35 to 500 mg/100 mL in the regular coffee drink (Farah, 2012). CGA esters are formed between cinnamic acids (caffeic acid, ferulic acid and p-coumaric acid) and quinic acid; here, any CGA ester will be referred as CGA (Clifford et al., 2017). Among them, 5-O-caffeyolquinic acid (Fig. 1) is the most studied CGA ester and is linked to the GCBE’s fat-lowering effects (Farias-Pereira et al., 2018). In addition, the CGA precursors (i.e. cinnamic acids) or its degraded products were related to antioxidant properties (Jeszka-Skowron et al., 2016; Kamiyama et al., 2015; Yue et al., 2019).

Trigonelline (Fig. 1), an alkaloid derivative of niacin (vitamin B3), is present at 40–50 mg/100 mL in regular coffee drink (Farah, 2012). Although there is limited evidence of the physiological effects of trigonelline, trigonelline has shown to have antioxidant and anti-inflammatory effects (Mohamadi et al., 2018). Additionally, trigonelline has shown to be potential anti-diabetes and anti-obesity agent, which may also be linked to niacin’s effects on lipid metabolism (Riedel et al., 2014; Sharma et al., 2018; Yoshinari et al., 2009).

Cafestol (Fig. 1) is one of the coffee diterpenes found at 0.25–0.3 mg/100 mL in the regular coffee drink, and up to 4 mg/100 mL in unfiltered coffee drink (Rendon et al., 2018). High amounts of cafestol intake increased blood cholesterol levels; daily intake of 60 mg cafestol increased about 30 mg/dL total cholesterol levels in humans after 28 days (Urgert et al., 1997). This is due to the fact that cafestol is an agonist of farnesoid X receptors (FXR), responsible for the increase of blood cholesterol levels by inhibiting bile acid synthesis (Post et al., 1997; Ricketts et al., 2007). On the other hand, cafestol has shown beneficial biological effects, such as anti-obesity, anti-diabetes, anticancer and anti-inflammatory properties (Lima et al., 2017; Mellbye et al., 2015, 2017; Shokouh et al., 2018; van Cruchten 2010).

Kahweol (Fig. 1), present at range of 0.14–0.2 mg/100 mL in the regular coffee drink, is another diterpene mostly found in Arabica coffee beans (Farah, 2012; Rendon et al., 2018). In vitro studies have shown that kahweol is a potential antioxidant, anti-obesity and anticancer agent (Baek et al., 2017; Lee and Jeong, 2007; Oh et al., 2018). Although kahweol and cafestol are structurally similar, their effects on lipid metabolism have been shown to be different; cafestol was more effective as cholesterol-raising factor, while kahweol was more effective as an adipogenesis inhibitor (Baek et al., 2017; Urgert et al., 1997).

Coffee regulates lipid metabolism

Coffee and human health

Human studies have shown that moderate consumption of coffee (2–3 cups/day) is associated with reduced risk of metabolic syndrome, obesity and type 2 diabetes (Grosso et al., 2017; Santos and Lima, 2016). Daily consumption of coffee (510 mg CGA and 120 mg caffeine) or GCBE (372 mg CGA and 14.48 mg caffeine) ameliorated some parameters for metabolic syndrome after 8 weeks, including reduced body fat and insulin resistance (Roshan et al., 2018; Sarria et al., 2018). Consistently, daily intake of 600 mg CGA increased fat oxidation in healthy male subjects after 5 days (Park et al., 2017).

The effects of coffee are influenced by genetic differences in the population; i.e., rate of caffeine metabolism contributed significantly to physiological responses to coffee (Palatini et al., 2015; Robertson et al., 2018). Daily intake of coffee (174.4 mg CGA and 175.2 mg caffeine) reduced postprandial glucose levels in people who metabolizes caffeine slowly, but increased postprandial glucose levels in people who metabolize caffeine quickly after 12 weeks (Robertson et al., 2018). However, a follow-up study reported that hypertensive patients who metabolize caffeine slowly had higher risk of impaired fasting glucose, compared to whom metabolize caffeine quickly or non-coffee drinkers (Palatini et al., 2015).

A systematic review of clinical trials has discussed inconsistent results of different types of coffee on glucose metabolism and suggested that CGA and other compounds than caffeine within coffee contribute to the coffee’s effects on human health (Reis et al., 2019). For instance, a cross-over study showed that decaffeinated coffee (equivalent to 17–24 mg caffeine or 0.24–0.33 mg caffeine/kg body weight), but not caffeinated coffee (equivalent to 101–144 mg caffeine or 1.4–2.0 mg caffeine/kg body weight), improved insulin sensitivity in healthy men (Reis et al., 2018). Therefore, many of the inconsistent effects of coffee on human health may be due to variation of coffee composition.

Although some epidemiological studies show that moderate coffee consumption is associated with reduced risk of cardiovascular diseases, whether coffee has adverse or beneficial effects on blood lipids profile and its mechanisms is still being investigated (Godos et al., 2014; Poole et al., 2017; Saeed et al., 2019). A meta-analysis showed that coffee consumption (2.4–8 cups/day) increased total cholesterol, low-density lipoproteins (LDL) and triglycerides levels after 2–11 weeks (Grosso et al., 2017). Others have shown that coffee has a null or beneficial effect on lipid profile; coffee or GCBE did not have an impact on lipid profile in healthy subjects (Robertson et al., 2018; Roshan et al., 2018), while coffee reduced blood triglycerides levels in subjects with high cholesterol levels after 8 weeks (Sarria et al., 2018). In addition, unfiltered coffee was strongly associated with the undesirable changes in lipid profile, probably due to inhibitory effects of cafestol on bile acid synthesis (Saeed et al., 2019; Urgert et al., 1997). Overall, these human trials provide limited evidence that coffee and its bioactive compounds regulate lipid metabolism. This review will summarize the current proposed mechanisms of action of coffee and its bioactive compounds on lipid metabolism (Tables 1 and 2).

Table 1.

Summary of mechanistic studies of coffee extracts on lipid metabolism

Material Dosesa Time (day) Model Effectsb Targetsc References
Green coffee bean extracts 5 mg/mL (50% CGA and 2% caffeine) 3 Caenorhabditis elegans ↓TG ↓ACC; ↑ACS2; ↑ECH4; ↑FOXO; ↓FAR4; ↑HSL; ↓SREBP Farias-Pereira et al. (2018)
1% diet (27% CGA and 10% caffeine) 14 ddY mice (♂) ↓b.w.; ↓TG ↑CPT Shimoda et al. (2006)
330 mg/kg b.w. (p.o.) (28% CGA and 9% caffeine) 70 High fat diet-fed ICR and C57BL/6 mice (♂) ↓b.w.; ↓Chol; ↓HDL; ↓Leptin; ↓TG ↓ACRP30; ↓PPARγ Kim et al. (2014)
200 mg/kg b.w. (p.o.) (50% CGA) 42 High fat diet-fed C57BL/6 J mice (♂) ↑Adiponectin; ↓b.w.; ↓Chol; ↓FFA; ↓Glucose; ↓LDL; ↓Leptin; ↓TG ↑AMPK; ↑ATGL; ↓C/EBPα; ↑CPT1; ↓FAS; ↑HSL; ↑PPARα; ↓PPARγ; ↓SREBP1c; ↓SREBP2 Choi et al. (2016)
Water extracts 1% diet (77% CGA) 14–105 High fat diet-fed C57BL/6 J mice (♂) ↓b.w.; ↓Chol; ↑Energy expenditure; ↓Glucose; ↓Inflammation; ↓Insulin; ↓Leptin; ↓TG ↓ACC1; ↓ACC2; ↓FAS; ↑miR-122; ↓SREBP1c; ↓SCD1; ↑UCP2 Murase et al. (2010)
0.5% water 70 High fat diet -fed Swiss mice (♂) ↑Adiponectin; ↓Glucose; ↓Inflammation; ↓Insulin; ↑Leptin ↑PKB Caria et al. (2014)
2% diet 63 High fat diet-fed C57BL/6 mice (♂) ↓b.w.; ↓Inflammation; ↓Insulin; ↓TG ↓SCD1 Jia et al. (2014)
0.1% water 119 Aged C57BL/6 NCr mice (♂) ↑ATP; ↓FFA; ↑Locomotor activity; ↓TG ↓mTOR; ↑PPARα Takahashi et al. (2017)
1 g/kg b.w. (p.o.) (1.2% CGA and 0.4% caffeine) 84 High fat diet-fed Wistar rats (♂) ↓b.w.; ↓Chol; ↓Insulin; ↓LDL; ↓TG ↑LXRα; ↓NPC1L1; ↑PPARα; ↓PPARγ Ontawong et al. (2019a, b)
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ab.w., body weight; p.o., per os

b↓, decrease; ↑, increase; b.w., body weight; Chol, cholesterol; FFA, free fatty acids; TG, triglycerides

cACC, acetyl-CoA carboxylase; ACRP, adipocyte complement-related protein; AMPK, AMP-activated protein kinase; ATGL, adipose triglyceride lipase; C/EBP, CCAAT/enhancer binding protein; CPT, carnitine palmitoyl transferase; ECH, enoyl-CoA hydratase; FAR, fatty acid- and retinoid-binding protein; FAS, fatty acid synthase; FOXO, forkhead box O; HSL, hormone sensitive lipase; LXR, liver X receptor; miR, microRNA; mTOR, mammalian target of rapamycin; NPC1L1, NPC1-like intracellular cholesterol transporter 1; PKB, protein kinase B; PPAR, peroxisome proliferator activated receptor; SCD, stearoyl-CoA desaturase; SREBP, sterol regulatory element-binding protein; UCP, uncoupling protein

Table 2.

Summary of mechanistic studies of coffee bioactive compounds on lipid metabolism

Material Dosesa Time (day) Model Effectsb Targetsc References
Cafestol 0.05% diet 56 High fat diet-fed C57BL6/J mice (♂) ↓Bile acids; ↓b.w.; ↑FFA ↑Glycerol; ↓Inflammation; ↓Insulin; ↓Leptin; ↓TG ↑ATGL; ↑CPT1; ↓FAS; ↑HSL; ↓SREBP1c; ↑UCP1 van Cruchten (2010)
Caffeine 5% 20 Zebrafish ↓b.w.; ↓TG ↓ACC1; ↑ACOX; ↓ATG12; ↓BECN1; ↓CD36; ↓SREBP1; ↓UCP2 Zheng et al. (2015)
60 mg/kg b.w. (s.c.) 4 h Obese yellow KK mice (♀) ↑Adrenaline; ↑FFA ↑UCP1; ↑UCP2; ↑UCP3 Kogure et al. (2002)
30 mg/kg b.w (i.p.); 0.05% water 3–28 C57BL/6 mice (♂) ↓b.w.; ↓TG ↑ACC; ↓CPT1α; ↑LC3; ↓mTOR; ↓SQSTM1 Sinha et al. (2014)
20 mg/kg b.w. (p.o.) 70 High energy diet-fed C57BL/6 mice (♂) ↓b.w.; ↓Chol ↓FFA; ↓TG ↓ACC; ↑AMPK; ↑cAMP Zhang et al. (2015)
20 mg/kg b.w. (p.o.) 42 High fat diet-fed Sprague–Dawley rats (♂) ↓b.w.; ↓TG ↓ACC; ↓FAS; ↑IRS1; ↑PPARα; ↓SREBP1c Liu et al. (2017)
60 mg/kg b.w. (p.o.) 11–14 High fat diet-fed C57BL/6; ob/ob mice (♂) ↓b.w.; ↓Glucose; ↓TG ↓A1R; ↑UCP1 Wu et al. (2017)
Chlorogenic acids 2.65 mg/mL 3 Caenorhabditis elegans ↓TG ↓ACC; ↓ACS2; ↑ECH4; ↓FAR4; ↑FOXO; ↓C/EBP; ↓SREBP Farias-Pereira et al. (2018)
80 mg/kg b.w. (i.p.) 56 High fat diet -fed hamsters (♂) ↓b.w.; ↓Chol; ↓FFA; ↓Glucose; ↓HDL; ↓Insulin; ↓LDL; ↓TG ↑HL; ↓LPL; ↑PPARα Li et al. (2009)
0.02% diet 56 High fat diet-fed ICR mice (♂) ↑Adiponectin; ↓b.w.; ↓Chol; ↓FFA; ↓Insulin; ↓Leptin; ↓TG ↓ACAT; ↓FAS; ↓HMGR; ↑PPARα Cho et al. (2010)
250 mg/kg b.w. (i.p) 14 Leprdb/db mice (♂) ↑Adiponectin; ↓b.w.; ↓Chol; ↓FFA; ↓Glucose; ↓Insulin; ↓TG ↓ACC; ↑AMPK; ↑CaMKK Ong et al. (2013)
90 mg/kg b.w. (p.o.) 84 High fat diet-fed Sprague–Dawley rats (♂) ↓b.w.; ↓Chol; ↓FFA; ↓Glucose; ↓Insulin; ↓HDL; ↓LDL; ↓TG ↓ACC; ↓CD36; ↑CPT2; ↓FABP4; ↓FAS; ↓LPL; ↓LXRα; ↑PPARα; ↑RXRα Huang et al. (2015)
100 mg/kg b.w. (i.p.) 42–105 High fat diet-fed C57BL/6 mice (♂) ↓b.w.; ↓Chol; ↓FFA; ↓Glucose; ↓Insulin; ↓TG ↑ACOX1; ↓CD36; ↑CPT1; ↓FABP4; ↓MGAT; ↑PPARα; ↓PPARγ Ma et al. (2015)
150 mg/kg b.w (p.o.) 42 High fat diet-fed Sprague–Dawley rats (♂) ↓b.w.; ↓Chol; ↓FFA; ↓TG ↓ACC; ↑AMPK; ↑CPT1 Sudeep et al. (2016)
150 mg/kg b.w. (p.o.) 42 High fat diet-fed ICR mice (♂) ↑Adiponectin; ↓b.w.; ↓Chol; ↑HDL; ↓LDL; ↓TG ↓C/EBPα; ↓FABP4; ↓FAS; ↓LPL; ↓SREBP1c; ↑PPARα; ↓PPARγ Wang et al. (2019)
Trigonelline 0.056% diet 43 Goko rats (♂) ↓Bile acid; ↓Chol; ↓FFA; ↓Glucose; ↓Insulin; ↓TG ↓FAS Yoshinari et al. (2009)
50 mg/kg b.w. (p.o.) 30 Alloxan-induced diabetes Wistar rats (♂) ↑b.w.; ↓Chol; ↓Glucose; ↑HDL; ↓LDL; ↓TG ↓Intestinal Lipase Hamden et al. (2013)
50 mg/kg b.w (p.o.) 112 High fat (or cholesterol) diet-fed C57BL/6 J mice (♂) ↓b.w.; ↓Chol; ↓Glucose ↓Insulin; ↓TG ↑AMPK; ↑BECN1; ↓CD36; ↓mTOR; ↓PPARγ; ↓SREBP1 Sharma et al. (2018)
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ab.w., body weight; i.p, intraperitoneal; p.o., per os; s.c., subcutaneous

b↓, decrease; ↑, increase; b.w., body weight; Chol, cholesterol; FFA, free fatty acids; TG, triglycerides

cA1R, adenosine 1 receptor; ACAT, acyl-CoA cholesterol acyltransferase; ACC, acetyl-CoA carboxylase; ACOX, acyl-CoA oxidase; AMPK, AMP-activated protein kinase; ATG, autophagy related; ATGL, adipose triglyceride lipase; BECN, beclin; C/EBP, CCAAT/enhancer binding protein; cAMP, cyclic AMP; CaMKK, calcium/calmodulin-dependent protein kinase kinase; CD, cluster of differentiation; CPT, carnitine palmitoyl transferase; ECH, enoyl-CoA hydratase; FABP, fatty acid-binding protein; FAR, fatty acid- and retinoid-binding protein; FAS, fatty acid synthase; FOXO, forkhead box O; HL, hepatic lipase; HMGR, HMG-CoA reductase; HSL, hormone sensitive lipase; IRS, insulin receptor substrate; LC, microtubule-associated protein 1A/1B-light chain; LPL, lipoprotein lipase; LXR, liver X receptor; MGAT, monoacylglycerol acyltransferase; mTOR, mammalian target of rapamycin; PPAR, peroxisome proliferator activated receptor; RXR, retinoid X receptor; SREBP, sterol regulatory element-binding protein; UCP, uncoupling protein

Coffee reduces lipogenesis

Coffee has shown to have fat-lowering effects in humans, which was associated with reduced lipogenesis (Santos and Lima, 2016). Coffee extracts (Choi et al., 2016; Farias-Pereira et al., 2018; Jia et al., 2014; Murase et al., 2010), CGA (Cho et al., 2010; Farias-Pereira et al., 2018; Huang et al., 2015; Ong et al., 2013; Sudeep et al., 2016; Zheng et al., 2014), caffeine (Liu et al., 2017; Sinha et al., 2014; Zheng et al., 2014, 2015), trigonelline (Yoshinari et al., 2009) and cafestol (van Cruchten 2010) have shown to reduce activity of key enzymes for lipogenesis: acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS) and/or stearoyl-CoA desaturase (SCD). ACC and FAS are responsible for the first two steps of de novo lipogenesis, while SCD for the synthesis of monounsaturated fatty acids for fat storage (Proenca et al., 2014). The enzymatic inhibitory effects of coffee and/or its bioactive compounds were in part via regulation of upstream transcription factors for lipogenesis: CCAAT/enhancer-binding proteins (C/EBP), peroxisome proliferator-activated receptors (PPAR, especially PPARγ), and/or sterol regulatory element-binding proteins (SREBP) (Choi et al., 2016; Farias-Pereira et al., 2018; Kim et al., 2014; Liu et al., 2017; Ma et al., 2015; Murase et al., 2010; Ontawong et al., 2019a; Sharma et al., 2018; van Cruchten 2010; Wang et al., 2019; Zheng et al., 2014; Zheng et al., 2015). These transcription factors are well-known to regulate adipogenesis, including lipogenesis (Chung et al., 2016; Proenca et al., 2014).

In addition, coffee reduces lipogenesis by regulating another metabolic pathway, AMP-activated protein kinase (AMPK), which inhibits ACC and FAS (Ong et al., 2013; Proenca et al., 2014). In fact, coffee, CGA, caffeine and trigonelline were able to activate AMPK (Egawa et al., 2011; Mathew et al., 2014; Ong et al., 2013; Sharma et al., 2018; Sudeep et al., 2016; Wei Ong et al., 2012; Zhang et al., 2015). Many factors regulate AMPK activity, including the second messenger cyclic AMP (cAMP), which is increased by caffeine (Zhang et al., 2015). Along with increased cAMP, caffeine and CGA activated Ca2+/calmodulin-dependent protein kinase (CaMK), which can subsequently regulate the AMPK activation (Egawa et al., 2011; Mathew et al., 2014; Ong et al., 2013).

Coffee can also activate the forkhead box O (FOXO), involved in the insulin-signaling pathway known to regulate lipogenesis. GCBE and CGA reduced body fat dependent to increased FOXO nuclear translocation, leading to an decreased lipogenesis in Caenorhabditis elegans (Farias-Pereira et al., 2018). These suggest that the fat-lowering effects of coffee by inhibition of lipogenesis are potentially from its effects on insulin-mediated pathway via FOXO.

Epigenetic modifications by coffee might contribute to its effects on lipogenesis as well; coffee and CGA upregulated miR-122, a microRNA abundant in the liver with the inhibition of SREBP, ACC and FAS in murine hepatocytes (Murase et al., 2010). Similarly, others reported that coffee increased miR-96, a microRNA involved in SREBP expression in human intestinal epithelial Caco-2 cells (Jeon et al., 2013; Nakayama et al., 2017). Therefore, coffee and its bioactive compounds may inhibit lipogenesis via epigenetic changes.

Coffee compounds regulate lipid uptake and transport

Coffee can regulate the fatty acid translocase (FAT/CD36/SR-B2), a key transmembrane protein for lipid uptake and transport (Marechal et al., 2018). Caffeine, CGA and trigonelline have shown to decrease the diet-induced hepatic CD36 overexpression (Huang et al., 2015; Ma et al., 2015; Sharma et al., 2018; Zheng et al., 2015). CD36 is not only important for the uptake of dietary fatty acids, but also its ability to bind lipoproteins in the liver (Calvo et al., 1998; Ramasamy, 2014). Thus, the decreased expression of CD36 by coffee compounds is probably related to changes in blood lipid profile, including reduced triglycerides, cholesterol and LDL levels (Huang et al., 2015; Ma et al., 2015; Sharma et al., 2018; Zheng et al., 2015). It was further suggested that caffeine, CGA and trigonelline regulated CD36 via AMPK- and PPARγ -dependent pathways (Huang et al., 2015; Ma et al., 2015; Marechal et al., 2018; Quan et al., 2013; Sharma et al., 2018).

Other lipid-binding proteins involved in lipid uptake and transport, such as fatty acid-binding proteins (FABP) and fatty acid transporters proteins (FATP), were regulated by coffee bioactive components (Baek et al., 2017; Farias-Pereira et al., 2018; Lally et al., 2012; Su et al., 2013). It is suggested that the decreased lipid uptake and transport is related to lipogenesis inhibition; FABP4 (also called aP2), a target for PPARγ, was downregulated by caffeine and kahweol in adipocytes (Baek et al., 2017; Su et al., 2013). Consistently, a fatty acid- and retinoid-binding protein, FAR-4, was required for GCBE and CGA to reduce fat accumulation in C. elegans (Farias-Pereira et al., 2018). However, coffee compounds can increase lipid uptake and transport in the muscle driven by fatty acid β-oxidation; caffeine increased lipid uptake and transport in muscle tissue by regulating FABP, FATP1 and FATP4, partially dependent on mitochondrial CD36 (Lally et al., 2012). Taken together, coffee bioactive compounds regulate tissue-specific lipid uptake and transport via CD36 and other lipid-binding proteins.

Coffee increases fatty acid β-oxidation

There are many reports of coffee and its bioactive compounds on regulating fatty acid β-oxidation (Cho et al., 2010; Choi et al., 2016; Farias-Pereira et al., 2018; Huang et al., 2015; Li et al., 2009; Liu et al., 2017; Ma et al., 2015; Shimoda et al., 2006; Sinha et al., 2014; Sudeep et al., 2016; van Cruchten 2010; Wang et al., 2019; Zheng et al., 2014, 2015). Coffee, CGA, caffeine and cafestol have shown to increase the rate-limiting enzyme for mitochondrial fatty acid β-oxidation, carnitine palmitoyl transferase (CPT), which transports acyl-CoA from cytosol into mitochondria (Choi et al., 2016; Huang et al., 2015; Ma et al., 2015; Shimoda et al., 2006; Sinha et al., 2014; Sudeep et al., 2016; van Cruchten 2010). In addition, peroxisomal fatty acid β-oxidation was increased by CGA and/or caffeine via regulation of acyl-CoA oxidases (ACOX), the first step of the peroxisomal fatty acid β-oxidation (Ma et al., 2015; Reddy and Hashimoto, 2001; Zheng et al., 2014, 2015).

It is suggested that coffee regulates enzymes of fatty acid β-oxidation by activating PPARα in the liver and adipose tissues (Cho et al., 2010; Choi et al., 2016; Huang et al., 2015; Li et al., 2009; Liu et al., 2017; Ma et al., 2015; Ontawong et al., 2019a; Wang et al., 2019). Moreover, PPARβ/δ, involved in the fatty acid β-oxidation in muscle tissue, may play a role in the coffee’s effects; caffeine upregulated PPARβ/δ in muscle cells (Chung et al., 2016; Schnuck et al., 2018). However, it was reported that a coffee extract and CGA did not act as PPAR agonists in kidney CV-1 cells (Murase et al., 2010). Therefore, the mechanism in which coffee and its bioactive compounds activate PPAR is yet to be clear.

Other nuclear hormone receptors are reported to be involved in the coffee bioactive components’ effects on fatty acid β-oxidation. For instance, CGA has shown to increase expression of retinoid X receptor (RXR) and decrease liver X receptor (LXR) (Huang et al., 2015), which share similarities with PPARα (Boergesen et al., 2012). There is evidence that cafestol acts as a FXR agonist (Ricketts et al., 2007); FXR is not only involved in cholesterol metabolism, but involved in fatty acid β-oxidation (Massafra and van Mil, 2018; Yang et al., 2019). Thus, it is possible that cafestol and CGA regulate fatty acid β-oxidation via FXR, RXR and LXR. Therefore, it can be considered that coffee has pleiotropic effects by regulating transcription factors that potentially impact fatty acid β-oxidation.

Coffee regulates lipolysis

Coffee and caffeine consumption increased lipolysis, measured by free fatty acids and/or glycerol, peaking after 2–4 h in humans (Flanagan et al., 2014; Mougios et al., 2003; Vandenberghe et al., 2016). It was suggested that caffeine increases lipolysis in adipose tissue by inhibiting adenosine receptor and increasing catecholamine levels via the sympathetic nervous system (Carrageta et al., 2018; Kogure et al., 2002; Wu et al., 2017). The lipolytic effects of caffeine are mediated by the increased cAMP levels that activate enzymes for lipolysis, especially hormone-sensitive lipases (HSL) (Carrageta et al., 2018; Proenca et al., 2014; Zhang et al., 2015). Consistently, GCBE, CGA and cafestol upregulated HSL and adipose triglyceride lipases, both responsible for lipolysis in adipose tissue (Choi et al., 2016; Peng et al., 2018; van Cruchten 2010). However, GCBE, not CGA, upregulated HSL expression in C. elegans (Farias-Pereira et al., 2018). Since post-transcriptional regulation of these enzymes is important (Liu et al., 2018), the effects of coffee and its compounds on lipase’s activities will need to be determined to confirm the activities of coffee on lipolysis.

The lipolytic effects of coffee compounds are regulated by an additional pathway, the mammalian target of rapamycin (mTOR) (Caron et al., 2015). mTOR was inhibited by coffee, caffeine, trigonelline and kahweol in vivo or in vitro (Oh et al., 2018; Sharma et al., 2018; Sinha et al., 2014; Takahashi et al., 2017). Consistently, the lipolytic effects of caffeine were related to autophagy-lysosomal pathway dependent on AMPK and CaMK, known to cross-talk with mTOR (Mathew et al., 2014; Sinha et al., 2014). Therefore, the effects of coffee and its compounds on the nutrient-sensing pathways mTOR, AMPK and CaMK may contribute to the effects of coffee on lipolysis.

Coffee reduces lipid digestion

Coffee and its bioactive compounds may reduce dietary lipid digestion, partially due to inhibition of digestive lipase (Cha et al., 2012; Noh et al., 2006; Ontawong et al., 2019b). GCBE inhibits pancreatic lipase activity, in which half-maximal inhibitory concentration (IC50) was estimated to be 1.98 mg/mL in in vitro digestive simulation (Cha et al., 2012; Narita et al., 2012). The inhibitory effects of lipase by coffee is more likely due to CGA than caffeine; IC50 for CGA was 13–287 µM and IC50 for caffeine was > 500 µM (Cha et al., 2012). Trigonelline was also found to inhibit lipase and other digestive enzymes in rats (Hamden et al., 2013). GCBE inhibited pancreatic lipase by decreasing surface area of lipid emulsion and increasing lipid droplet size in vitro (Narita et al., 2012).

Coffee bioactive compounds can also affect lipid digestion by reducing the function or synthesis of bile acids, emulsifying agents that enhance lipid digestion (Ontawong et al., 2019b; Post et al., 1997). CGA was able to bind bile acids in vitro, suggesting that it reduces the function of bile acid on lipid digestion (Ontawong et al., 2019b). Moreover, cafestol was found to inhibit bile acid synthesis in rodents, which potentially changes lipid digestion (Post et al., 1997; Ricketts et al., 2007). Therefore, the inhibition of bile acid synthesis and lipase activity by coffee and its bioactive compounds may reduce dietary lipid digestion.

In conclusion, coffee and its bioactive components have shown to regulate lipid metabolism. Although there is more evidence for coffee extracts, especially GCBE, CGA and caffeine, other, less studied compounds (trigonelline, cafestol and kahweol) have shown potential to act on lipid metabolism in vivo and/or in vitro studies. Many questions about their mechanisms on lipid metabolism remain to be answered, and perhaps with the use of ‘omics’ technologies in humans, we will be able to understand and validate the effects of coffee on human health in future.

Acknowledgements

This work was financially supported by the Brazilian National Counsel of Technological and Scientific Development [CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico]. The authors thank Mr. Joshua Barsczewski for his assistance editing this manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest to disclose.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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