Effects of fructose-containing sweeteners on fructose intestinal, hepatic, and oral bioavailability in dual-catheterized rats.

ObjectiveFructose is commonplace in Western diets and is consumed primarily through added sugars as sucrose or high fructose corn syrup. High consumption of fructose has been linked to the development of metabolic disorders, such as cardiovascular diseases. The majority of the harmful effects of fructose can be traced to its uncontrolled and rapid metabolism, primarily within the liver. It has been speculated that the formulation of fructose-containing sweeteners can have varying impacts on its adverse effects. Unfortunately, there is limited data supporting this hypothesis. The objective of this study was to examine the impact of different fructose-containing sweeteners on the intestinal, hepatic, and oral bioavailability of fructose.MethodsPortal and femoral vein catheters were surgically implanted in male Wistar rats. Animals were gavaged with a 1 g/kg carbohydrate solution consisting of fructose, 45% glucose/55% fructose, sucrose, glucose, or water. Blood samples were then collected from the portal and systemic circulation. Fructose levels were measured and pharmacokinetic parameters were calculated.ResultsCompared to animals that were gavaged with 45% glucose/55% fructose or sucrose, fructose-gavaged animals had a 40% greater fructose area under the curve and a 15% greater change in maximum fructose concentration in the portal circulation. In the systemic circulation of fructose-gavaged animals, the fructose area under the curve was 17% and 24% higher and the change in the maximum fructose concentration was 15% and 30% higher than the animals that received 45% glucose/55% fructose or sucrose, respectively. After the oral administration of fructose, 45% glucose/55% fructose, and sucrose, the bioavailability of fructose was as follows: intestinal availability was 0.62, 0.53 and 0.57; hepatic availability was 0.33, 0.45 and 0.45; and oral bioavailability was 0.19, 0.23 and 0.24, respectively.ConclusionsOur studies show that the co-ingestion of glucose did not enhance fructose absorption, rather, it decreased fructose metabolism in the liver. The intestinal, hepatic, and oral bioavailability of fructose was similar between 45% glucose/55% fructose and sucrose

Bioactivity-Guided Identification of Botanical Inhibitors of Ketohexokinase.

OBJECTIVE:In developed countries with westernized diets, the excessive consumption of added sugar in beverages and highly refined and processed foods is associated with increased risk for obesity, diabetes, and cardiovascular diseases. As a major constituent of added sugars, fructose has been shown to cause a variety of adverse metabolic effects, such as impaired insulin sensitivity, hypertriglyceridemia, and oxidative stress. Recent studies have shown that ketohexokinase isoform C is the key enzyme responsible in fructose metabolism that drive's fructose's adverse effects. The objective of this study was to identify botanical ingredients with potential for inhibitory activity against ketohexokinase-C and fructose-induced metabolic effects by using a series of in vitro model systems. METHODS:Extracts from 406 botanicals and 1200 purified phytochemicals were screened (initial concentration of 50 μg/mL and 50 μM, respectively) for their inhibitory activity using a cell free, recombinant human ketohexokinase-C assay. Dose response evaluations were conducted on botanical extracts and phytochemicals that inhibited ketohexokinase-C by > 30% and > 40%, respectively. Two different extract lots of the top botanical candidates were further evaluated in lysates of HepG2 cells overexpressing ketohexokinase-C for inhibition of fructose-induced ATP depletion. In addition, extracts were evaluated in intact Hep G2 cells for inhibition of fructose-induced elevation of triglyceride and uric acid production. RESULTS:Among the botanical extracts, phloretin (Malus domestica) extracts were the most potent (IC50: 8.9-9.2 μg/mL) followed by extracts of Angelica archangelica (IC50: 22.6 μg/mL-57.3 μg/mL). Among the purified phytochemicals, methoxy-isobavachalcone (Psoralea corylifolia, IC50 = 0.2 μM) exhibited the highest potency against ketohexokinase isoform C activity followed by osthole (Angelica archangelica, IC50 = 0.7 μM), cratoxyarborenone E (Cratoxylum prunifolium, IC50 = 1.0 μM), and α-/γ-mangostin (Cratoxylum prunifolium, IC50 = 1.5 μM). Extracts of Angelica archangelica, Garcinia mangostana, Petroselinum crispum, and Scutellaria baicalensis exhibited ketohexokinase inhibitory activity and blocked fructose-induced ATP depletion and fructose-induced elevation in triglyerides and uric acid. CONCLUSIONS:Angelica archangelica, Garcinia mangostana, Petroselinum crispum, and Scutellaria baicalensis were the top four botanical candidiates identified with inhibitory activity against ketohexokinase-C. Future studies are needed to show proof of mechanism and the efficacy of these botanical extracts in humans to blunt the negative metabolic effects of fructose-containing added sugars

Inhibitory Activity of Extracts of Top Botanical Candidates.

<p>Inhibitory Activity of Extracts of Top Botanical Candidates.</p

HPLC gradient conditions.

<p>HPLC gradient conditions.</p

Cell viability after exposure to top botanical candidates.

<p>MTT assay was utilized to determine % cell viability of Hep G2 cells after 72 hr exposure to increasing doses of the top four botanical extracts (Lot #1). (A) <i>Angelica archangelica</i>, (B) <i>Scutellaria baicalensis</i>, (C) <i>Petroselinum crispum</i>, and (D) <i>Garcinia mangostana</i>.</p

3-Step recombinant ketohexokinase enzymatic assay.

<p>KHKC Ketohexokinase C isoform. PK pyruvate kinase. LDH lactate dehydrogenase.</p

Inhibitory KHKC Activity of Candidate Botanical Extracts.

<p>Inhibitory KHKC Activity of Candidate Botanical Extracts.</p

HPLC chromatograms of extracts of top botanical candidates.

<p>(A) <i>Angelica archangelica</i>, (B) <i>Scutellaria baicalensis</i>, (C) <i>Petroselinum crispum</i>, and (D) <i>Garcinia mangostana</i>. The arrows indicate the marker compounds. A1: osthenol, A2: osthole, B1: baicalin, C1: apiin, and D1: α-/γ-mangostin.</p

Impact of Genetic Polymorphisms of <em>SLC2A2</em>, <em>SLC2A5</em>, and <em>KHK</em> on Metabolic Phenotypes in Hypertensive Individuals

<div><h3>Objective</h3><p>In the past few decades, consumption of added sugars has increased dramatically. Studies have linked high sugar intake with increased risk for a number of diseases. Importantly, fructose, a component of sugar, has been linked with the development of features of metabolic syndrome. This study determined if single nucleotide polymorphisms in genes involved in fructose transport (solute carrier family 2 facilitated glucose transporter, member 2 (<em>SLC2A2</em>) and solute carrier family 2 facilitated glucose/fructose transporter, member 5 (<em>SLC2A5</em>)) and metabolism (ketohexokinase (<em>KHK</em>)) affect inter-individual variability in metabolic phenotypes, such as increased serum uric acid levels.</p> <h3>Materials/Methods</h3><p>The influence of <em>SLC2A2</em>, <em>SLC2A5</em>, and <em>KHK</em> SNPs on metabolic phenotypes was tested in 237 European Americans and 167 African Americans from the Pharmacogenomic Evaluation and Antihypertensive Responses (PEAR) study. Using baseline untreated fasting data, associations were considered significant if p≤0.005. These SNPs were then evaluated for potential replication (p≤0.05) using data from the Genetic Epidemiology of Responses to Antihypertensives (GERA) studies.</p> <h3>Results</h3><p><em>SLC2A5</em> rs5438 was associated with an increase in serum uric acid in European American males. However, we were unable to replicate the association in GERA. The minor allele of <em>SLC2A2</em> rs8192675 showed an association with lower high-density lipoproteins in European Americans (A/A: 51.0 mg/dL, A/G: 47.0 mg/dL, G/G: 41.5 mg/dL, p = 0.0034) in PEAR. The association between rs8192675 and lower high-density lipoproteins was replicated in the combined European American GERA study samples (A/A: 47.6 mg/dL, A/G: 48.6 mg/dL, G/G: 41.9 mg/dL, p = 0.0315).</p> <h3>Conclusions</h3><p>The association between <em>SLC2A2</em> rs8192675 and high-density lipoproteins suggests the polymorphism may play a role in influencing high-density lipoproteins and thus metabolic risk of cardiovascular disease.</p> </div