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PharmaNutrition 3 (2015) 4652

Contents lists available at ScienceDirect

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journal homepage: www.elA R T I C L E I N F O

Article history:Received 22 January 2015Received in revised form 27 February 2015Accepted 3 March 2015

Keywords:HopsIsohumulonesMetabolic inammationInsulin resistance

A B S T R A C T

The lipophilic extracts of the common hops (Humulus lupulus) contain compounds that are readilymodied to the family of isohumulones (e.g., iso-alpha acids). The isohumulones have been found toreduce metabolic inammation and insulin resistance, and positively impact dyslipidemia and obesity.These effects are consistent across studies in multiple cell lines, animal model systems and humanintervention trials. Mechanistic work has demonstrated that these isohumulones have a uniquepleiotropic mechanism of action which is consistent with their demonstrated safety and range ofphysiological effects. It is suggested from this extensive body of work that specic isohumulones may beimportant bioactive agents for the application in medical nutrition therapy in the support of diseasesassociated with chronic inammation and insulin resistance.

2015 Published by Elsevier B.V.

Contents

1. Inuence of hops isohumulones (iso-alpha acids) on inammation and insulin sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472. Bioavailability and metabolism of isohumulones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493. Effects of hops isohumulones on insulin sensitivity and metabolic syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494. Inuence of the hops-derived isohumulones on obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

The past two decades have witnessed a global explosion in theprevalence of non-communicable, non-infectious chronic diseasessuch as type 2 diabetes, coronary heart disease, autoimmunediseases, and dementia [1]. All of these diseases have been found tobe associated with a physiological state of chronic inammationdened as low-grade inammation orchestrated by metabolic cellsin response to specic immune activating signals [2], the origin ofwhich is complex but has been found to be related to diet, lifestyleand environmental factors [3]. The recent PREDIMED study hasdemonstrated that a Mediterranean diet rich in fruit andvegetables, whole grains, nuts and virgin olive oil has a benecialinuence on lowering the incidence of heart disease and reducingchronic metabolic inammation [48].

This association between specic dietary components and thereduction in incidence of non-communicable chronic diseases

* Corresponding author. Tel.: +1 2069222912.E-mail address: jeffbland@kindexpharmaceuticals.com (J.S. Bland).

http://dx.doi.org/10.1016/j.phanu.2015.03.0012213-4344/ 2015 Published by Elsevier B.V.Review

Isohumulones from hops (Humulus lupunutrition therapy

Jeffrey S. Bland a,*, Deanna Minich b, Robert LermanMatthew Tripp b, Neile Grayson a

aKinDex Pharmaceuticals, Seattle, Washington, USAbConsultant Scientist, Seattle, Washington, USAs) and their potential role in medical

, Gary Darland b, Joseph Lamb b,

utrition

sevier .com/ locate /phanu

raises the question as to the mechanistic role that specic diets andtheir component nutrients have on chronic diseases associatedwith metabolic inammation. It is well known that food iscomposed of a complex matrix of the macronutrients protein,carbohydrate and fat that exist in many different chemical andphysical forms depending on the type of foods and their method ofpreparation that are included in the diet. Beyond these nutrients,however, vitamins, minerals, essential fatty acids, phytochemicalsand conditionally essential nutrients such as taurine, lipoic acid,coenzyme Q10, and carnitine all play roles in the modulation ofphysiological function.

Micronutrients and phytonutrients have been found to inu-ence physiology through the following cellular interactions [9,10]:

B-vitamins serve as cofactors to specic enzymes that regulatemetabolism.

Minerals serve as cofactors that regulate enzyme activities. Fat soluble vitamins A and D have been demonstrated toinuence genetic expression as well as non-genomic effects.

Essential amino acids such as phenylalanine, tyrosine andtryptophan serve as precursors to neurotransmitters.

Phytochemicals can serve as agents that modulate intercellularsignal transduction and genetic expression.

1. Inuence of hops isohumulones (iso-alpha acids) oninammation and insulin sensitivity

One of the interesting families of phytochemicals in terms oftheir inuence on cellular disturbances associated with metabolicinammation and insulin resistance as reviewed by Van Cleemputet al. are the lipophilic isohumulones (e.g., iso-alpha acids) derivedfrom the common hops, Humulus lupulus [17].

The resin glands or strobiles of the female hop plantbiosynthesize several hundred different phytochemicals. Thehumulones or alpha acids represent one major class of lipophilicagents produced by the female plant, and have been used asbittering agents in the production of beer for centuries. In thebrewing of beer, the heating process involved in the developmentof the wort can isomerize the cyclohexadienone structure of thehumulones to the cyclopentadienone structure of the isohumu-lones as shown in Fig. 2. The degree of isomerization and theamount of bitter avor produced by the addition of hops is highlydependent on the length of time the hops are boiled.

Yajima et al. were the rst group to report the inuence thatisohumulones have in both cellular and animal models of insulinresistance [18]. Their published study included the results of asmall double blind, placebo controlled pilot trial in diabetichumans demonstrating a signicant reduction in fasting blood

mic

J.S. Bland et al. / PharmaNutrition 3 (2015) 4652 47Over the past decade phytochemicals have been identied thatinuence metabolism, signal transduction and genetic expressionthrough a number of specic mechanisms that include [1115]:

Nuclear transcription factor regulation. Epigenetic regulation. Response element inuence. Mitochondrial redox regulation. Enzyme inhibition. Precursor to cellular mediators. Post-translational protein modication.

Howitz and Sinclair have suggested that the role of phyto-chemicals in inuencing mammalian physiology is through ahormetic effect (i.e., low dose benecial modulatory effect) onsignal transduction and genetic expression that reduces cellularstress response as described in Fig. 1 [16].

Fig. 1. Inuence of various phytocheglucose and hemoglobin A1c after 8 weeks of intervention in theisohumulone treated group versus the control group. Subsequentstudies reported by this Japanese group indicated that thehops-derived isohumulones reduced elevated triglycerides asso-ciated with insulin resistance, and raised HDL cholesterol levelswhile reducing liver fat stores in diabetic animal models [19,20]. Ina companion study this same group reported that the administra-tion of isohumulones prevented high fat diet-induced obesity inthe C57BL/6N mouse model [21]. Nozawa et al. also reported thatdietary supplementation with isohumulones was found to reducethe production of the proinammatory prostaglandin E2 in the ratcolon suggesting a tissue-specic anti-inammtory effect [22].

In 2005 Tripp reported the unique antiinammatory potentialand putative mechanism of action of the isohumulones [23,24].Babish et al. screened 208 chemically characterized phytochemicalextracts for antiinammatory and antidiabetic activity and foundthat the iso-alpha acids derived from hops and proanthocyanidins

als on cellular stress response [16].

activated cells without adversely inuencing cyclooxygenase2 expression in other cells such as the gastrointestinal mucosawhere this enzyme is important for maintaining healthy function.It was shown by Hall et al. in the AGS human gastric mucosal cellline that the isohumulones do not have an adverse effect oncyclooxygenase function whereas the common non-steroidalantiinammatories aspirin, ibuprofen, indomethacin and nap-roxen increase the risk to gastrointestinal pathology due to theirinhibition of cyclooxygenase function [33]. In human interventiontrials the isohumulone pharmacophore had no effect on the level offecal calprotectin, a measure of gastric inammation, whenadministered orally, whereas naproxen in the same subjects in acrossover trial resulted in a signicant increase in fecal calprotectin

to isohumulone in the brewing of beer.

48 J.S. Bland et al. / PharmaNutrition 3 (2015) 4652from Acacia nilotica were among the most active naturalcompounds inuencing both inammation and insulin signalingpathways [25]. Indeed, a synergistic relationship between theisohumulones derived from hops and A. nilotica- derivedproanthocyanidins was observed at specic ratios and mayrepresent an example of how combination of specic phytochem-icals can have a hormetic inuence on cellular physiology [26].

Hougee et al. have described the inuence of lipophilic hops-extracts on the reduction of zymosan-induced arthritis in themouse model [27]. Minich and Bland discuss the role of the hopsisohumulones and other phytochemicals on signal transductionassociated with regulation of the insulin and inammationmetabolic network [28].

The isohumulones are the major constituents of modied hopextracts which is an approved food additive in the United States forthe use as bittering agents in beer [29]. The chemical structures ofthe cis and trans isomers of the three classes of isohumulonestermed n, co and ad are as shown:

Fig. 2. Isomerization of hops humuloneThe isohumulones have been found effective in reducinginammatory arthritis in both animal models and open labeland controlled human intervention trials in individuals with thepain and inammation associated with osteoarthritis to improvesymptoms as determined by the use of the WOMAC validatedosteoarthritis screening questionnaire [30,31].

The safety of the hops-derived isohumulones as contrasted tothe standard non-steroidal anti-inammatory medications isrelated to the unique antiinammatory mechanism of action ofthe isohumulones. Hall et al. have demonstrated that theisohumulones are not a direct inhibitor of the proinammatoryenzyme cyclooxygenase 2, but rather they reduce the nucleartranslocation of the transcription factor NFkB selectively inimmune activated macrophages [32]. The isohumulones reducethe abundance of the inducible cyclooxygenase 2 in the immune[33,34].Mechanistic studies executed by Konda et al. demonstrated that

the isohumulones had a dose dependent impact on both NFkBnuclear translocation and nitric oxide production in LPS stimulatedRAW 264.7 murine macrophages as shown in Fig. 3 indicating thatthe anti-inammatory effect of the isohumulones was a result ofdecreased inammatory gene expression [35].Fig. 3. Inuence of the hops-derived RIAA on NFkB and nitric oxide synthaseactivity [35].

oxidized low density lipoprotein more effectively than the lowglycemic load, Mediterranean diet alone [46].

Lerman et al. reported that in women and men with metabolicsyndrome, insulin resistance and dyslipidemia that interventionwith the medical food containing the hops-derived isohumulonesand A. nilotica anthocyanidins along with a low glycemic load,Mediterranean style diet resulted in signicantly better outcome inreduction of all the clinical features of metabolic syndrome than ina matched group of subjects who received the low glycemic load,Mediterranean diet alone [47].

4. Inuence of the hops-derived isohumulones on obesity

Sumiyoshi and Kimura reported that extracts of hops(H. lupulus) were found to inhibit obesity in mice fed a high fatdiet over a long-term period [48]. They proposed that specic hopextracts might be useful for preventing obesity and glucoseintolerance caused by a high fat diet.

In examining the inuence of isohumulones on obesity, Kondaet al. reported that a specic molecule synthesized from theisohumulone THIAA mixture had the ability to improve insulinsignaling and obesity in both the diet-induced obesity mousemodel of type 2 diabetes and the Zucker diabetic fatty rat model[49]. This study demonstrated that the isohumulone pharmaco-phore represents itself as a privileged structure that inuencesadipocyte physiology and adiposity.

Vroegriik et al. demonstrated that the hops-derived isohumu-lone mixture when administered in a high-fat fed mouse model ofdiabetes for 514 weeks resulted in a signicantly lower mean

J.S. Bland et al. / PharmaNutrition 3 (2015) 4652 49Desai et al. demonstrated that the isohumulone derivativeTHIAA attenuates the TNF-alpha activated inammation andmatrix metalloproteinase-9 expression in human monocyticTHP-1 cells as well as their adherence to human aortic endothelialcells [36]. These observations suggest that THIAA may havebenecial effects for the prevention of cardiovascular diseases byameliorating inammation and subsequent plaque destabilization,which are hallmarks of atherosclerosis. Desai et al. have alsoreported that the THIAA derivative from hops was capable ofreducing the inammatory processes associated with an animalmodel of rheumatoid arthritis by showing a reduction in swelling,prevention of cartilage destruction, and reduction in bonedestruction [36].

2. Bioavailability and metabolism of isohumulones

Cattoor et al. evaluated the bioavailability of the isohumulonesin New Zealand white rabbits and well as in Caco-2 cell monolayersto investigate epithelial transport. The bioavailability of theisohumulones was determined through the differential pharma-cokinetics of an oral versus intravenously administered dose. Theisohumulones were found to be efciently transported across thegastrointestinal mucosa resulting in approximately 30% absorptionof an oral dose within 4 h after administration [37,38].

When the isohumulones were incubated with rabbit hepaticmicrosomes it was found that they were rapidly metabolized to avariety of oxidation products principally characterized as humu-linic acids and allosio-alpha-acids which are water soluble andreadily excreted [39].

In studies with Dahl salt-sensitive hypertensive rats it wasfound that when they were fed a diet supplemented withisohumulones that there was a marked reduction observed inrenal injury, proteinuria and blood pressure. It was also found thatglomerulosclerosis and interstitial brosis scores were signicant-ly decreased. The authors suggest that the exposure to isohumu-lones and their metabolites may help prevent the progression ofrenal injury caused by hypertension [40].

3. Effects of hops isohumulones on insulin sensitivity andmetabolic syndrome

Over the past decade the interrelationship between theinammatory and insulin signaling pathways has been elucidated[41]. In vitro assays with murine 3T3L1 adipocytes as well diabeticanimal models indicated that the antiinammatory effects of theisohumulones were associated with the improvement in insulinsignaling [42,43]. Obara et al. reported the results of a study ofninety-four subjects with prediabetes who were randomly dividedinto four groups and engaged in a 12 week double blind dose-nding study to evaluate the impact of ingestion of 16, 32, or 48 mgof isohumulones per day versus placebo [44]. After treatment thefasting blood glucose was decreased in the 32 and 48 mg groups,but did not change in the placebo group. The hemoglobin A1c wasalso signicantly decreased in the 48 mg group versus the placebo.There was also a signicant decrease in body mass index (BMI) inthe 48 mg group as compared with placebo.

In a 12 week, diet controlled intervention trial in patients withmetabolic syndrome and dyslipidemia it was found that a medicalfood supplemented program containing isohumulones and Acaciaanthocyandins resulted in a clinical improvement in all thebiomarkers associated with insulin resistance [45]. In a largermulti-centered, diet controlled study in women with insulinresistance and metabolic syndrome Jones et al. found that anisohumulone and anthocyanidin containing medical food admin-istered along with a low glycemic load, Mediterranean dietdecreased atherogenic lipoproteins and lipoprotein (a) andweight than the control animals or those treated with the insulinsensitizing drug rosiglitazone even though calorie consumptionwas equal in all three groups as shown in Fig. 4 [50].

In metabolic chamber studies they found that the isohumu-lones increased thermogenic responsiveness and resting energyexpenditure in the animals suggesting that the isohumulonesincrease lipid metabolism.

Fig. 4. Effect of the isohumulone mixture (Meta060) and rosiglitazone interventionon obesity in the high fat fed diabetic mouse model [50].

These observations that the isohumulones are associated withimproved lipid metabolism, improved insulin sensitivity and thereduction in metabolic inammation raises the question as to amechanistic explanation for these varied inuences on metabolicdisturbance. Everard et al. have provided a novel potentialexplanation for the various inuences that the isohumuloneshave on these multiple physiological endpoints [51]. Theyevaluated the inuence of isohumulones in the high-fat fedmouse model of diabetes on insulin sensitivity, serum triglycer-ides, inammation and obesity. Their data conrmed previousstudies that demonstrated the ability of the isohumulones toimprove insulin action and its relationship to the regulation ofpost-prandial serum glucose, and the reduction of triglyceridesand obesity.

Beyond these observations, however, Cani et al. demonstratedthat the isohumulones were capable of reducing post-prandialendotoxemia. There is now considerable evidence that high fatdiets create alteration in gut mucosal permeability and activationof the enteric immune system that initiates metabolic inamma-tion and insulin resistance [5254]. This state of chronicpostprandial endotoxemia in turn results in systemic crosstalkamong the intestinal microbiota, circulating macrophages andmonocytes, adipocytes and skeletal muscle that creates a bluntingof insulin sensitivity and reduced lipid metabolism [55,56].Characteristics of postprandial endotoxemia include an increasein serum lipopolysaccharides derived from the outer cellularmembrane of intestinal gram negative bacteria and the proin-ammatory cytokines TNF-alpha and interleukin-6 [57]. The work

50 J.S. Bland et al. / PharmaNutrition 3 (2015) 4652of Cani et al. demonstrated in the diet-induced obesity mousemodel that the administration of isohumulones resulted in a trendtoward a statistically signicant reduction of plasma lipopolysac-charides, however the reduction in postprandial serum levels ofinterleukin-6 and tumor necrosis factor alpha did reach statisticalsignicance [51].

It is known that the high fat diet increases gastrointestinalmucosal permeability through the alteration in integrity of thetight junction proteins, occludin and zonulin, which then

Fig. 5. Inuence of isohumulones (Meta) on gastrointestinal mucosal occludin andzonulin mRNA in the high fat fed obese mouse model [51].contributes to the increased absorption of LPS and activation ofthe enteric immune system [58,59]. As is shown in Fig. 5, Cani et al.demonstrated that the administration of isohumulones improvedzonulin and occludin mRNA expression in the gastrointestinalmucosa in the high-fat fed obese mouse model which is consistentwith improved gastrointestinal mucosal integrity and a reducedabsorption of LPS [51].

These data suggest that isohumulones may reduce the activationof specic pattern recognition receptors on target tissues such as thegastrointestinal mucosal cells thereby reducing the triggering of theproinammatory immune response which is associated with insulinresistance, dyslipidemia, and obesity [60,61].

5. Conclusion

The lipophilic family of isohumulones derived from a modiedhops extract have been found to have a unique ability to modulatethe metabolic disturbances that result in chronic metabolicinammation. These effects have been demonstrated consistentlyamong various cell lines, animal model systems and humanintervention trials. The isohumulones improve insulin resistanceand dyslipidemia in humans. They have also been shown to reducesystemic inammation, increase lipid metabolism and reduceadiposity in high fat-fed animal models. Lastly they have beenshown to reduce post-prandial endotoxemia while improvinggastrointestinal mucosal integrity during high fat feeding in animalmodels. These characteristics of this class of molecules indicatethat the isohumulones position themselves as potentially useful asbioactive substances for inclusion in medical nutrition therapiesfor the management of chronic diseases associated with metabolicinammation related diabesity [62]. The emerging understandingof the physiological effects of the isohumulones suggests that theyhave a pleiotropic network inuence on metabolism. As Barabasihas recently commented network effects increasingly affect allaspects of biologic and medical research, from disease mechanismsto drug discovery. It is only a matter of time until these advances inunderstanding will start to affect medical practice, making theemergence of a new eld that may be aptly called networkmedicine [63]. The isohumulones represent a family of moleculesthat may well nd applications in medical nutrition therapy due totheir unique pleiotropic inuences on the chronic diseasesassociated with metabolic inammation.

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Isohumulones from hops (Humulus lupulus) and their potential role in medical nutrition therapy1 Influence of hops isohumulones (iso-alpha acids) on inflammation and insulin sensitivity2 Bioavailability and metabolism of isohumulones3 Effects of hops isohumulones on insulin sensitivity and metabolic syndrome4 Influence of the hops-derived isohumulones on obesity5 ConclusionReferences