Ferulic acid attenuates high-fat diet-induced hypercholesterolemia by activating classic bile acid synthesis pathway

Abstract

Ferulic acid (FA), a natural phenolic phytochemical abundantly present in whole grains, displays promising therapeutic effects on hypercholesterolemia while its underlying mechanism not fully elucidated. This study aimed to investigate the cholesterol-lowering effect of FA in high-fat diet (HFD)-fed mice and its potential molecular mechanism. FA supplementation alleviated HFD-induced hypercholesterolemia (–13.2%, p < 0.05), along with increased excretion of bile acids (BAs) in feces (37.0%, p < 0.05). Mechanism studies showed that FA activated the expression of cholesterol 7α hydroxylase (CYP7A1), a rate-limiting enzyme in BA biosynthesis in the liver, which increased the BAs biosynthesis from cholesterol. Surprisingly, increased excretion of BAs in feces is a consequence, not a cause, of CYP7A1 activation. Furthermore, enterohepatic farnesoid X receptor (FXR) signaling is not involved in the activation of hepatic CYP7A1 by FA. In conclusion, FA activates CYP7A1 through non-FXR signaling, which on the one hand effectively prevents hypercholesterolemia, and on the other hand leads to secondary BAs elevation in plasma. The latter may be the key to the anti-obesity and hypoglycemic effects of FA.

Punicalagin alleviates hypercholesterolemia in mice through modulating farnesoid X receptor signaling and modulating gut microbiota

“…For example, a dietary intake of soybean soluble polysaccharide can reduce hepatic lipid accumulation and attenuate obesity via the PPAR signaling pathway [41] . Ferulic acid supplementation alleviated HFD-induced hypercholesterolemia by increased the BAs biosynthesis from cholesterol through activation of Cyp7a1 [42] . FXR is highly expressed in both hepatocytes and intestinal enterocytes and is endogenously activated by BAs, where it regulates many aspects of BA metabolism such as synthesis, export into the bile ducts, and intestinal reabsorption [43] .…”

Diversity of Bioactive Metabolites Produced by Thermophilic Bacillus Strains Isolated from Jordanian Hot Springs

“…This suggests that these thermophilic Bacillus strains may produce compounds with potential antimicrobial applications, which is highly relevant in the context of antibiotic resistance. Compound 7, ferulic acid exhibits antioxidant, anti-inflammatory properties and is known for its strong cholesterol-lowering effects (Bumrungpert et al, 2018;Srinivasan et al, 2007;Thapliyal et al, 2021), aligning with the interest in natural compounds for managing hypercholesterolemia and related health concerns (Ghaisas et al, 2014;Luo et al, 2022;Kwon et al, 2009). The identification of uracil, and 3-methyl uracil further enriches the repertoire of isolated compounds, plying fundamental roles in genetics DNA replication, and their analogs offering potential applications in chemotherapy and antiviral drugs (Jordheim et al, 2013;Ladner 2001;Seley-Radtke and Yates 2018).…”

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“…This suggests that these thermophilic Bacillus strains may produce compounds with potential antimicrobial applications, which is highly relevant in the context of antibiotic resistance. Compound 7, ferulic acid exhibits antioxidant, anti-inflammatory properties and is known for its strong cholesterol-lowering effects (Bumrungpert et al, 2018;Srinivasan et al, 2007;Thapliyal et al, 2021), aligning with the interest in natural compounds for managing hypercholesterolemia and related health concerns (Ghaisas et al, 2014;Luo et al, 2022;Kwon et al, 2009). The identification of uracil, and 3-methyl uracil further enriches the repertoire of isolated compounds, plying fundamental roles in genetics DNA replication, and their analogs offering potential applications in chemotherapy and antiviral drugs (Jordheim et al, 2013;Ladner 2001;Seley-Radtke and Yates 2018).…”