Nutr Res Pract.  2025 Apr;19(2):200-214. 10.4162/nrp.2025.19.2.200.

p-Coumaric acid alleviates metabolic dysregulation in high-fructose diet-fed hamsters

• Yoon HJ
• Jung UJ

• KMID: 2566809
• DOI: http://doi.org/10.4162/nrp.2025.19.2.200

Abstract

BACKGROUND/OBJECTIVES
p-Coumaric acid (CA), a 4-hydroxycinnamic acid derivative, is widely distributed in nature and exerts various beneficial biological effects. However, the effects of CA on metabolic abnormalities triggered by excessive fructose intake, such as dyslipidemia, hyperglycemia, non-alcoholic fatty liver disease (NAFLD), and insulin resistance, have not been sufficiently investigated. Our objective was to investigate whether CA ameliorates high-fructose diet (HFrD)-induced metabolic dysregulation.
MATERIALS/METHODS
Golden Syrian hamsters were randomly assigned to 3 groups and were fed diets containing 60% cornstarch (CON group), 60% fructose (HFrD group), or 60% fructose with CA (0.02%) (HFrD+CA group) for 5 weeks.
RESULTS
HFrD feeding significantly increased the levels of plasma triglyceride, apolipoprotein (apo)-CIII, fasting blood glucose, and homeostatic model assessment insulin resistance, and tended to increase plasma total cholesterol (TC) and low-density lipoprotein/very low-density lipoprotein cholesterol (LDL/VLDL-C) compared with the CON group. In HFrD-fed hamsters, CA supplementation significantly decreased plasma TC, LDL/VLDL-C, apo-CIII, and fasting blood glucose levels. Moreover, CA significantly decreased the hepatic lipid levels and fibrosis induced by HFrD. The plasma and hepatic lipid-lowering effects of CA were associated with decreased enzyme activity and mRNA expression of genes involved in fatty acid, triglyceride, and cholesterol synthesis as well as increased activity of carnitine palmitoyltransferase, a rate-limiting enzyme in fatty acid oxidation, in the liver. CA-treated hamsters also exhibited decreased hepatic gluconeogenic enzyme activity and increased hepatic glycolytic enzyme activity, with mRNA expression changes similar to these activity patterns.
CONCLUSION
Our findings indicate that CA potentially improves metabolic abnormalities associated with excessive fructose intake, such as hyperglycemia, dyslipidemia, and NAFLD.

Keyword

Fructose; hyperglycemia; dyslipidemias; non-alcoholic fatty liver disease; p-coumaric acid

Figure

• 

  Fig. 1 Effects of CA supplementation on food intake (A), body weight (B), food efficiency ratio (C), body weight gain (D), and epididymal white adipose tissue weight (E) in Golden Syrian hamsters fed a HFrD. Data are presented as mean ± SE of the mean. Values are compared between groups using Student’s t-test.CA, p-coumaric acid; HFrD, high-fructose diet; CON, control diet; FER, food efficiency ratio; WAT, white adipose tissue; NS, no significant.##P < 0.01, CON group versus HFrD group; *P < 0.05, **P < 0.01, HFrD group versus HFrD+CA group.

• 

  Fig. 2 Effects of CA supplementation on fasting blood glucose (A), plasma insulin (B), HOMA-IR (C), plasma TG (D), TC (E), LDL/VLDL-C (F), HDL-C (G), FFA (H), HTR (I), AI (J), and Apo-CIII (K) levels in Golden Syrian hamsters fed a HFrD. Data are presented as mean ± SE of the mean. Values are compared between groups using Student’s t-test.CA, p-coumaric acid; HOMA-IR, homeostatic index of insulin resistance; TG, triglyceride; TC, total cholesterol; LDL/VLDL-C, low-density lipoprotein/very low-density lipoprotein-cholesterol; HDL-C, high-density lipoprotein-cholesterol; FFA, free fatty acid; HTR, ratio of HDL-C to TC; AI, atherogenic index; apo-CIII, apolipoprotein CIII; CON, control diet; HFrD, high-fructose diet; NS, no significant.#P < 0.05, ##P < 0.01, CON group versus HFrD group; *P < 0.05, HFrD group versus HFrD+CA group.

• 

  Fig. 3 Effects of CA supplementation on liver weight (A), hepatic TG (B), hepatic TC (C), hepatic FFA (D), histopathological staining of liver section (E), fecal TG (F), and fecal TC (G) in Golden Syrian hamsters fed a HFrD. Data are presented as mean ± SE of the mean. Values are compared between groups using Student’s t-test.CA, p-coumaric acid; TG, triglyceride; TC, total cholesterol; FFA, free fatty acid; CON, control diet; HFrD, high-fructose diet; NS, no significant.#P < 0.05, ##P < 0.01, CON group versus HFrD group; *P < 0.05, HFrD group versus HFrD+CA group.

• 

  Fig. 4 Effects of CA supplementation on activities of enzymes (A-C) and mRNA expression of genes (D-M) involved in lipid synthesis or decomposition in the liver of Golden Syrian hamsters fed a HFrD. Data are presented as mean ± SE of the mean. Values are compared between groups using Student’s t-test.CA, p-coumaric acid; HFrD, high-fructose diet; CON, control diet; PAP, phosphatidate phosphatase; CPT, carnitine palmitoyltransferase; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; SCD1, stearoyl-CoA desaturase 1; SREBP1c, sterol regulatory element-binding protein-1c; PPAR-α, peroxisome proliferator-activated receptor alpha; SREBP2, sterol regulatory element-binding protein-2; HMGCR, 3-hydroxy-3-methylglutaryl coenzyme A reductase; HMGCS, 3-hydroxy-3-methylglutaryl coenzyme A synthase; CPT1a, carnitine palmitoyltransferase 1a; NS, no significant.##P < 0.01, CON group versus HFrD group; *P < 0.05, **P < 0.01, ***P < 0.001, HFrD group versus HFrD+CA group.

• 

  Fig. 5 Effects of CA supplementation on hepatic glucose metabolic enzymes activities (A-C) and genes mRNA expression (D-F) in Golden Syrian hamsters fed a HFrD. Data are presented as mean ± SE of the mean. Values are compared between groups using Student’s t-test.CA, p-coumaric acid; HFrD, high-fructose diet; CON, control diet; G6pase, glucose 6-phosphatase; PEPCK, phosphoenolpyruvate carboxykinase; NS, no significant.#P < 0.05, ##P < 0.01, CON group versus HFrD group; *P < 0.05, HFrD group versus HFrD+CA group.

Reference

1. Chew NWS, Ng CH, Tan DJH, Kong G, Lin C, Chin YH, Lim WH, Huang DQ, Quek J, Fu CE, et al. The global burden of metabolic disease: data from 2000 to 2019. Cell Metab. 2023; 35:414–428.e3. PMID: 36889281.

2. Johnson RJ, Segal MS, Sautin Y, Nakagawa T, Feig DI, Kang DH, Gersch MS, Benner S, Sánchez-Lozada LG. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr. 2007; 86:899–906. PMID: 17921363.

3. Basciano H, Federico L, Adeli K. Fructose, insulin resistance, and metabolic dyslipidemia. Nutr Metab (Lond). 2005; 2:5. PMID: 15723702.

4. Taskinen MR, Packard CJ, Borén J. Dietary fructose and the metabolic syndrome. Nutrients. 2019; 11:1987. PMID: 31443567.

5. Pei K, Ou J, Huang J, Ou S. p-Coumaric acid and its conjugates: dietary sources, pharmacokinetic properties and biological activities. J Sci Food Agric. 2016; 96:2952–2962. PMID: 26692250.

6. Yoon DS, Cho SY, Yoon HJ, Kim SR, Jung UJ. Protective effects of p-coumaric acid against high-fat diet-induced metabolic dysregulation in mice. Biomed Pharmacother. 2021; 142:111969. PMID: 34333285.

7. Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957; 226:497–509. PMID: 13428781.

8. Hulcher FH, Oleson WH. Simplified spectrophotometric assay for microsomal 3-hydroxy-3-methylglutaryl CoA reductase by measurement of coenzyme A. J Lipid Res. 1973; 14:625–631. PMID: 4147523.

9. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72:248–254. PMID: 942051.

10. Bieber LL, Fiol C. Purification and assay of carnitine acyltransferases. Methods Enzymol. 1986; 123:276–284. PMID: 3702720.

11. Lazarow PB. Assay of peroxisomal beta-oxidation of fatty acids. Methods Enzymol. 1981; 72:315–319. PMID: 7031421.

12. Walton PA, Possmayer F. Mg2-dependent phosphatidate phosphohydrolase of rat lung: development of an assay employing a defined chemical substrate which reflects the phosphohydrolase activity measured using membrane-bound substrate. Anal Biochem. 1985; 151:479–486. PMID: 3006539.

13. Davidson AL, Arion WJ. Factors underlying significant underestimations of glucokinase activity in crude liver extracts: physiological implications of higher cellular activity. Arch Biochem Biophys. 1987; 253:156–167. PMID: 3813560.

14. Alegre M, Ciudad CJ, Fillat C, Guinovart JJ. Determination of glucose-6-phosphatase activity using the glucose dehydrogenase-coupled reaction. Anal Biochem. 1988; 173:185–189. PMID: 2847588.

15. Bentle LA, Lardy HA. Interaction of anions and divalent metal ions with phosphoenolpyruvate carboxykinase. J Biol Chem. 1976; 251:2916–2921. PMID: 1270433.

16. Kang SI, Shin HS, Kim HM, Hong YS, Yoon SA, Kang SW, Kim JH, Ko HC, Kim SJ. Anti-obesity properties of a Sasa quelpaertensis extract in high-fat diet-induced obese mice. Biosci Biotechnol Biochem. 2012; 76:755–761. PMID: 22484945.

17. Kang SW, Kang SI, Shin HS, Yoon SA, Kim JH, Ko HC, Kim SJ. Sasa quelpaertensis Nakai extract and its constituent p-coumaric acid inhibit adipogenesis in 3T3-L1 cells through activation of the AMPK pathway. Food Chem Toxicol. 2013; 59:380–385. PMID: 23810795.

18. Bahadoran Z, Mirmiran P, Azizi F. Dietary polyphenols as potential nutraceuticals in management of diabetes: a review. J Diabetes Metab Disord. 2013; 12:43. PMID: 23938049.

19. Espinosa RR, Inchingolo R, Alencar SM, Rodriguez-Estrada MT, Castro IA. Antioxidant activity of phenolic compounds added to a functional emulsion containing omega-3 fatty acids and plant sterol esters. Food Chem. 2015; 182:95–104. PMID: 25842314.

20. Nasr Bouzaiene N, Kilani Jaziri S, Kovacic H, Chekir-Ghedira L, Ghedira K, Luis J. The effects of caffeic, coumaric and ferulic acids on proliferation, superoxide production, adhesion and migration of human tumor cells in vitro. Eur J Pharmacol. 2015; 766:99–105. PMID: 26432689.

21. Ou SY, Luo YL, Huang CH, Jackson M. Production of coumaric acid from sugarcane bagasse. Innov Food Sci Emerg Technol. 2009; 10:253–259.

22. Pragasam SJ, Rasool M. Dietary component p-coumaric acid suppresses monosodium urate crystal-induced inflammation in rats. Inflamm Res. 2013; 62:489–498. PMID: 23420453.

23. Kai H, Obuchi M, Yoshida H, Watanabe W, Tsutsumi S, Park YK, Matsuno K, Yasukawa K, Kurokawa M. In vitro and in vivo anti-influenza virus activities of flavonoids and related compounds as components of Brazilian propolis (AF-08). J Funct Foods. 2014; 8:214–223.

24. Tanida I, Shirasago Y, Suzuki R, Abe R, Wakita T, Hanada K, Fukasawa M. Inhibitory effects of caffeic acid, a coffee-related organic acid, on the propagation of hepatitis C virus. Jpn J Infect Dis. 2015; 68:268–275. PMID: 25672401.

25. Femia AP, Caderni G, Vignali F, Salvadori M, Giannini A, Biggeri A, Gee J, Przybylska K, Cheynier V, Dolara P. Effect of polyphenolic extracts from red wine and 4-OH-coumaric acid on 1,2-dimethylhydrazine-induced colon carcinogenesis in rats. Eur J Nutr. 2005; 44:79–84. PMID: 15309424.

26. Singletary KW, Stansbury MJ, Giusti M, Van Breemen RB, Wallig M, Rimando A. Inhibition of rat mammary tumorigenesis by concord grape juice constituents. J Agric Food Chem. 2003; 51:7280–7286. PMID: 14640571.

27. Barros MP, Lemos M, Maistro EL, Leite MF, Sousa JP, Bastos JK, Andrade SF. Evaluation of antiulcer activity of the main phenolic acids found in Brazilian Green Propolis. J Ethnopharmacol. 2008; 120:372–377. PMID: 18930797.

28. Choi SW, Lee SK, Kim EO, Oh JH, Yoon KS, Parris N, Hicks KB, Moreau RA. Antioxidant and antimelanogenic activities of polyamine conjugates from corn bran and related hydroxycinnamic acids. J Agric Food Chem. 2007; 55:3920–3925. PMID: 17397179.

29. Luceri C, Giannini L, Lodovici M, Antonucci E, Abbate R, Masini E, Dolara P. p-Coumaric acid, a common dietary phenol, inhibits platelet activity in vitro and in vivo . Br J Nutr. 2007; 97:458–463. PMID: 17313706.

30. Park JB. N-coumaroyldopamine and N-caffeoyldopamine increase cAMP via beta 2-adrenoceptors in myelocytic U937 cells. FASEB J. 2005; 19:497–502. PMID: 15790999.

31. Bravo E, Cantafora A, Calcabrini A, Ortu G. Why prefer the golden Syrian hamster (Mesocricetus auratus) to the Wistar rat in experimental studies on plasma lipoprotein metabolism? Comp Biochem Physiol B. 1994; 107:347–355.

32. Stein Y, Dabach Y, Hollander G, Stein O. Cholesteryl ester transfer activity in hamster plasma: increase by fat and cholesterol rich diets. Biochim Biophys Acta. 1990; 1042:138–141. PMID: 2297517.

33. Dalbøge LS, Pedersen PJ, Hansen G, Fabricius K, Hansen HB, Jelsing J, Vrang N. A hamster model of diet-induced obesity for preclinical evaluation of anti-obesity, anti-diabetic and lipid modulating agents. PLoS One. 2015; 10:e0135634. PMID: 26266945.

34. Kasim-Karakas SE, Vriend H, Almario R, Chow LC, Goodman MN. Effects of dietary carbohydrates on glucose and lipid metabolism in golden Syrian hamsters. J Lab Clin Med. 1996; 128:208–213. PMID: 8765217.

35. Taghibiglou C, Carpentier A, Van Iderstine SC, Chen B, Rudy D, Aiton A, Lewis GF, Adeli K. Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular apoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model. J Biol Chem. 2000; 275:8416–8425. PMID: 10722675.

36. Rémillard P, Shen G, Milne R, Maheux P. Induction of cholesteryl ester transfer protein in adipose tissue and plasma of the fructose-fed hamster. Life Sci. 2001; 69:677–687. PMID: 11476189.

37. Wang L, Yu J, Walzem RL. High-carbohydrate diets affect the size and composition of plasma lipoproteins in hamsters (Mesocricetus auratus). Comp Med. 2008; 58:151–160. PMID: 18524173.

38. Alwahsh SM, Gebhardt R. Dietary fructose as a risk factor for non-alcoholic fatty liver disease (NAFLD). Arch Toxicol. 2017; 91:1545–1563. PMID: 27995280.

39. Livesey G, Taylor R. Fructose consumption and consequences for glycation, plasma triacylglycerol, and body weight: meta-analyses and meta-regression models of intervention studies. Am J Clin Nutr. 2008; 88:1419–1437. PMID: 18996880.

40. Mastrocola R, Collino M, Rogazzo M, Medana C, Nigro D, Boccuzzi G, Aragno M. Advanced glycation end products promote hepatosteatosis by interfering with SCAP-SREBP pathway in fructose-drinking mice. Am J Physiol Gastrointest Liver Physiol. 2013; 305:G398–G407. PMID: 23868406.

41. Schulze MB, Manson JE, Ludwig DS, Colditz GA, Stampfer MJ, Willett WC, Hu FB. Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women. JAMA. 2004; 292:927–934. PMID: 15328324.

42. Yadav H, Jain S, Yadav M, Sinha PR, Prasad GB, Marotta F. Epigenomic derangement of hepatic glucose metabolism by feeding of high fructose diet and its prevention by Rosiglitazone in rats. Dig Liver Dis. 2009; 41:500–508. PMID: 19196556.

43. Paquot N, Schneiter P, Jéquier E, Gaillard R, Lefèbvre PJ, Scheen A, Tappy L. Effects of ingested fructose and infused glucagon on endogenous glucose production in obese NIDDM patients, obese non-diabetic subjects, and healthy subjects. Diabetologia. 1996; 39:580–586. PMID: 8739918.

44. Li P, Zhu D. Clinical investigation of glucokinase activators for the restoration of glucose homeostasis in diabetes. J Diabetes. 2024; 16:e13544. PMID: 38664885.

45. Geidl-Flueck B, Gerber PA. Fructose drives de novo lipogenesis affecting metabolic health. J Endocrinol. 2023; 257:257.

46. Brownsey RW, Boone AN, Elliott JE, Kulpa JE, Lee WM. Regulation of acetyl-CoA carboxylase. Biochem Soc Trans. 2006; 34:223–227. PMID: 16545081.

47. Shimano H, Yahagi N, Amemiya-Kudo M, Hasty AH, Osuga J, Tamura Y, Shionoiri F, Iizuka Y, Ohashi K, Harada K, et al. Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes. J Biol Chem. 1999; 274:35832–35839. PMID: 10585467.

48. Shimada M, Hibi M, Nakagawa T, Hayakawa T, Field CJ. High-fructose diet-induced hepatic expression of the Scd1 gene is associated with increased acetylation of histones H3 and H4 and the binding of ChREBP at the Scd1 promoter in rats. Biomed Res. 2021; 42:85–88. PMID: 33840688.

49. Shimada M, Hibino M, Takeshita A. Dietary supplementation with myo-inositol reduces hepatic triglyceride accumulation and expression of both fructolytic and lipogenic genes in rats fed a high-fructose diet. Nutr Res. 2017; 47:21–27. PMID: 29241575.

50. Miyazaki M, Dobrzyn A, Man WC, Chu K, Sampath H, Kim HJ, Ntambi JM. Stearoyl-CoA desaturase 1 gene expression is necessary for fructose-mediated induction of lipogenic gene expression by sterol regulatory element-binding protein-1c-dependent and -independent mechanisms. J Biol Chem. 2004; 279:25164–25171. PMID: 15066988.

51. Horn CL, Morales AL, Savard C, Farrell GC, Ioannou GN. Role of cholesterol-associated steatohepatitis in the development of NASH. Hepatol Commun. 2022; 6:12–35. PMID: 34558856.

52. Min HK, Kapoor A, Fuchs M, Mirshahi F, Zhou H, Maher J, Kellum J, Warnick R, Contos MJ, Sanyal AJ. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metab. 2012; 15:665–674. PMID: 22560219.

53. Dolivo DM, Reed CR, Gargiulo KA, Rodrigues AE, Galiano RD, Mustoe TA, Hong SJ. Anti-fibrotic effects of statin drugs: a review of evidence and mechanisms. Biochem Pharmacol. 2023; 214:115644. PMID: 37321414.

54. Truong TMT, Seo SH, Chung S, Kang I. Attenuation of hepatic fibrosis by p-coumaric acid via modulation of NLRP3 inflammasome activation in C57BL/6 mice. J Nutr Biochem. 2023; 112:109204. PMID: 36400112.