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Therapeutic potential of carbonyl-scavenging carnosine derivative in metabolic disorders
Jacob M. Haus1 and John P. Thyfault2
1School of Kinesiology, University of Michigan, Ann Arbor, Michigan, USA.
2Department of Molecular and Integrative Physiology, University of Kansas Medical School, Kansas City, Kansas, USA.
Address correspondence to: John P. Thyfault, Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 2067 Hemenway, 3901 Rainbow Blvd., Kansas City, Kansas 66160, USA. Phone: 913.588.1790; Email: jthyfault@kumc.edu.
Find articles by Haus, J. in: JCI | PubMed | Google Scholar
1School of Kinesiology, University of Michigan, Ann Arbor, Michigan, USA.
2Department of Molecular and Integrative Physiology, University of Kansas Medical School, Kansas City, Kansas, USA.
Address correspondence to: John P. Thyfault, Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 2067 Hemenway, 3901 Rainbow Blvd., Kansas City, Kansas 66160, USA. Phone: 913.588.1790; Email: jthyfault@kumc.edu.
Find articles by Thyfault, J. in: JCI | PubMed | Google Scholar
Published October 22, 2018 - More info
J Clin Invest. 2018;128(12):5198–5200. https://doi.org/10.1172/JCI124304.
Copyright © 2018, American Society for Clinical Investigation
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Abstract
Sugar- and lipid-derived aldehydes are reactive carbonyl species (RCS) frequently used as surrogate markers of oxidative stress in obesity. A pathogenic role for RCS in metabolic diseases of obesity remains controversial, however, partly because of their highly diffuse and broad reactivity and the lack of specific RCS-scavenging therapies. Naturally occurring histidine dipeptides (e.g., anserine and carnosine) show RCS reactivity, but their therapeutic potential in humans is limited by serum carnosinases. Here, we present the rational design, characterization, and pharmacological evaluation of carnosinol, i.e., (2S)-2-(3-amino propanoylamino)-3-(1H-imidazol-5-yl)propanol, a derivative of carnosine with high oral bioavailability that is resistant to carnosinases. Carnosinol displayed a suitable ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and was determined to have the greatest potency and selectivity toward α,β-unsaturated aldehydes (e.g., 4-hydroxynonenal, HNE, ACR) among all others reported thus far. In rodent models of diet-induced obesity and metabolic syndrome, carnosinol dose-dependently attenuated HNE adduct formation in liver and skeletal muscle, while simultaneously mitigating inflammation, dyslipidemia, insulin resistance, and steatohepatitis. These improvements in metabolic parameters with carnosinol were not due to changes in energy expenditure, physical activity, adiposity, or body weight. Collectively, our findings illustrate a pathogenic role for RCS in obesity-related metabolic disorders and provide validation for a promising new class of carbonyl-scavenging therapeutic compounds rationally derived from carnosine.
Authors
Ethan J. Anderson, Giulio Vistoli, Lalage A. Katunga, Katsuhiko Funai, Luca Regazzoni, T. Blake Monroe, Ettore Gilardoni, Luca Cannizzaro, Mara Colzani, Danilo De Maddis, Giuseppe Rossoni, Renato Canevotti, Stefania Gagliardi, Marina Carini, Giancarlo Aldini
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Introduction
Studies examining the mechanisms that drive insulin resistance and hyperglycemia have been a particular area of focus because of the rising rates of type 2 diabetes. Accumulating evidence shows a variety of potential mechanisms including ectopic lipid storage, lipid intermediates, inflammation, and mitochondrial dysfunction that may play roles in driving insulin resistance and hyperglycemia. Additionally, oxidative stress is also believed to play an important role. Intracellular and circulating markers of oxidative stress have been shown to track with worsening glycemia, insulin resistance, and lipid profiles, while weight loss and exercise interventions which improve these outcome measures also lower markers of oxidative stress. Oxidatives stress remains on the “outside looking in,” because there is still a lack of direct mechanistic evidence elucidating its role in the induction of insulin resistance. A lack of firm evidence is likely due to the multiple types of oxidative stress due identified through various outcome measures in different tissues or in the circulation, the transient nature of oxidative reactions, the difficulty in assessing quality outcome measures and, most important, the small number of studies directly targeting specific types of oxidative stress to assess improvement in outcomes.
Reactive sugar- and lipid-derived aldehydes called reactive carbonyl species (RCS) are spontaneously formed during food preparation under high heat and as by-products of oxidative stress. These RCS damage proteins via the covalent modification of arginine, cystine, histidine, and lysine residues, as well as through the formation of adducts with DNA and phospholipids. A positive energy balance at the cellular level from an oversupply of either lipids or carbohydrates promotes oxidative stress and leads to an increased formation of RCS-modified proteins. In particular, the oxidation of n-6 polyunsaturated fatty acids (PUFAs) leads to the formation of the α, β-unsaturated carbonyl species hydroxynonenal (HNE) and acrolein (ACR), each of which have been highly studied because they react readily with cellular proteins. HNE tracks with worsening obesity and metabolic dysfunction, and there is some evidence to suggest that these protein modifications underlie mechanisms of insulin resistance, fibrosis, and elevated lipids. Since the original characterization of HNE by Esterbauer et al. (1), the subsequent research involving this chemical has led to progress in numerous neutralization strategies.
The natural defense against HNE-mediated carbonyl stress is detoxification through a combination of aldehyde dehydrogenases and a family of glutathione S-transferase enzymes that create a stable, water-soluble glutathione S-hydroxynonenal (GS-HNE) that is shuttled out of the cell (Figure 1). Importantly, l-carnosine, a naturally occurring dipeptide, also has the ability to scavenge intracellular RCS, forming unreactive covalent adducts (2, 3) which are then excreted in the urine (4), thus providing an additional mechanism of RCS detoxification. Naturally occurring l-carnosine has been shown to be reduced in obesity, leading to a greater susceptibility to RCS accumulation. l-carnosine supplementation has been effective in lowering RCS in rodent models; however, only a few studies have been performed in humans (2, 4–9). Recently, two separate carnosine supplementation interventions (2 g/d for 12 wk) were performed in overweight-obese subjects. De Courten and colleagues found that two-hour glucose and insulin levels after a 75-g oral glucose tolerance test were both lower after carnosine supplementation compared with placebo in individuals with impaired glucose tolerance (7). On the other hand, Regazonni and colleagues found that carnosine bioavailability was limited because of rapid degradation by the carnosinase enzyme in tissues and serum, and carnosine-ACR adducts were detected in the urine of all subjects (4). The latter study illustrates one of the main challenges in maintaining carnosinemia. Recent studies have explored targeting carnosinase, as low serum carnosinase activity, via polymorphism in the carnosine dipeptidase-1 (CNDP1) gene, protects patients with type 2 diabetes from diabetic nephropathy, and renal tissue carnosinase can be allosterically inhibited by administration of reduced glutathione (GSH), N-acetylcysteine, and cysteine in diabetic mice (10). Further, the novel agent carnostatine (SAN9812) was shown to be a potent and selective carnosinase inhibitor in animal models (11). However, it is unclear whether this or related compounds are being pursued for use in humans. These findings highlight the need for innovative developments in carnosine and RCS scavenging to treat metabolic disorders of obesity.
Figure 1Fates of the reactive carbonyl HNE as a result of overnutrition and metabolic stress. (i) HNE is a RCS that damages proteins at various amino acid residues to form either a Schiff base or a Michael adduct. (ii) HNE can be detoxified through natural defense mechanisms including aldehyde dehydrogenases or glutathione transferases, which create a stable product that is exported out of cells and cleared by renal mechanisms. (iii) Left: HNE can also be sequestered by carnosine, creating a stable HNE-carnosine adduct that is nonreactive. However, carnosine is degraded by carnosinases, which limit HNE sequestration in vivo. Right: To circumvent carnosine degradation via carnosinases, a next-generation carnosine derivative called carnosinol was created, which is resistant to carnosinase degradation and has strong affinity for RSC.
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