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. 2024 Dec 4;14(12):679.
doi: 10.3390/metabo14120679.

The Role of Beta-Hydroxybutyrate in Mitigating the Inflammatory and Metabolic Consequences of Uric Acid

Nicole P Remund  1 , John G Larsen  1 , Marley J Shin  1 , Cali E Warren  1 , Isabelle L Palmer  1 , Iris J Kim  1 , Elijah T Cooper-Leavitt  1 , Derek M Clarke  1 , Colson G Beus  1 , Richard J Johnson  2 , Juan A Arroyo  1 , Paul R Reynolds  1 , Benjamin T Bikman  1
Affiliations

The Role of Beta-Hydroxybutyrate in Mitigating the Inflammatory and Metabolic Consequences of Uric Acid

Nicole P Remund et al. Metabolites. .

Abstract

Background: Uric acid (UA), a metabolite of purine and fructose metabolism, is linked to inflammation and metabolic disorders, including gout and cardiovascular disease. Its pro-inflammatory effects are largely driven by the activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, leading to increased cytokine production. Beta-hydroxybutyrate (BHB), a ketone produced during fasting or carbohydrate restriction, has been shown to reduce inflammation. This study explores the role of BHB in mitigating the inflammatory and metabolic effects of elevated uric acid levels. Methods: We utilized a murine muscle cell culture treated with UA and BHB. Results: Muscle cells treated with UA had increased production of pro-inflammatory cytokines and reduced cell viability. Co-treatment with BHB reversed these effects, improving cell survival and reducing cytokine levels. Additionally, uric acid impaired mitochondrial function and increased oxidative stress, which were mitigated by BHB. Furthermore, uric acid disrupted insulin signaling, but BHB co-treatment restored insulin sensitivity. Conclusions: These findings suggest that BHB holds therapeutic potential by counteracting the inflammatory and metabolic disruptions caused by elevated uric acid, making it a promising target for conditions such as hyperuricemia and metabolic syndrome.

Keywords: inflammation; insulin resistance; ketones; mitochondria; uric acid.

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Conflict of interest statement

B.T.B., P.R.R., and R.J.J. are advisors for RxSugar. B.T.B. is an advisor for Unicity International and receives royalties from the sale of a book about insulin resistance.

Figures

Figure 1
Figure 1
Myoblasts were incubated for 24 h in either uric acid (500 µM), β-hydroxybutyrate (BHB; 5 mM), or both U + B (n = 10). Interferon-γ (IFN-γ; (A) and tumor necrosis factor-α (TNF-α; (B) were measured via dot blot. (C) NLRP3 activity was determined via activity assay. * p < 0.05 vs. CON. # p < 0.05 vs. UA.
Figure 2
Figure 2
Myoblasts were incubated for 24 h in either uric acid (500 µM), β-hydroxybutyrate (BHB; 5 mM), or both U + B. Cell viability was measured via the MTT assay (n = 8). * p < 0.05 vs. CON.
Figure 3
Figure 3
Myoblasts were incubated for 24 h in either uric acid (500 µM), β-hydroxybutyrate (BHB; 5 mM), or both U + B (n = 5). Mitochondrial respiration (A) was measured by the following strategy: GM indicates glutamate (10 mM) + malate (2 mM); +ADP (2.5 mM); +succinate (S; 10 mM); +FCCP (0.05 μM). H2O2 generation (B) was measured via Amplex Red. The ratio of H2O2 generation to O2 consumed (C) was also determined. * p < 0.05 for treatment versus CON. # p < 0.05 vs. UA.
Figure 4
Figure 4
Myoblasts were incubated for 24 h in either uric acid (500 µM), β-hydroxybutyrate (BHB; 5 mM), or both (U + B) followed by 10 min of insulin treatment (100 nM) (n = 5). Levels of phosphorylated Akt (pAkt; (A) and glycogen synthase kinase 3β (pGSK3β; (B) were measured compared with no insulin stimulation. * p < 0.05 for treatment vs. CON.
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