The effect of ursodeoxycholic acid on the relative expression of the lipid metabolism genes in mouse cholesterol gallstone models

Abstract

Background Many studies indicate that gallstone formation has genetic components. The abnormal expression of lipid-related genes could be the basis for particular forms of cholesterol gallstone disease. The aim of this study was to obtain insight into lipid metabolism disorder during cholesterol gallstone formation and to evaluate the effect of ursodeoxycholic acid (UDCA) on the improvement of bile lithogenicity and its potential influence on the transcription of lipid-related genes. Methods Gallstone-susceptible mouse models were induced by feeding with a lithogenic diet (LD) for 8 weeks. Bile and liver tissues were obtained from these mouse models after 0, 4 and 8 weeks. Bile lipids were measured enzymatically, and the cholesterol saturation index (CSI) was calculated to evaluate the bile lithogenicity by using Carey’s critical tables. Real-time polymerase chain reaction (RT-PCR) was used to detect the mRNA expression levels of farnesoid X receptor (FXR), liver X receptor (LXR), adenosine triphosphate-binding cassette subfamily G member 5/8 (ABCG5/8), cholesterol 7-α hydroxylase (CYP7A1), oxysterol 7-α hydroxylase (CYP7B1), sterol 27-α hydroxylase (CYP27A1), peroxisome proliferator-activated receptor alpha (PPAR-α) and adenosine triphosphate-binding cassette subfamily B member 11 (ABCB11). Results The rate of gallstone formation was 100% in the 4-week group but only 30% in the UDCA-treated group. The UDCA-treated group had a significantly lower CSI compared with other groups. Of special note, the data on the effects of UDCA showed higher expression levels of ABCG8, ABCB11 and CYP27A1, as well as lower expression levels of LXR and PPAR-α, compared to the model control group. Conclusions UDCA exhibits tremendously potent activity in restraining lipid accumulation, thus reversing the lithogenic effect and protecting hepatocytes from serious pathological damage. The abnormal expression of ABCG8, CYP7A1, CYP27A1, LXR and PPAR-α might lead to high lithogenicity of bile. These results are helpful in exploring new lipid metabolism pathways and potential targets for the treatment of cholesterol stones and for providing some basis for the study of the pathogenesis and genetic characteristics of cholelithiasis. Research on the mechanism of UDCA in improving lipid metabolism and bile lithogenicity may be helpful for clinical treatment and for reducing the incidence of gallstones.

Impact of Dietary Lipids on the Reverse Cholesterol Transport: What We Learned from Animal Studies

“…Other evidence supporting the previous mechanism as a driver of the cholesterolenhanced m-RCT comes from a recent paper [168], showing the upregulation of hepatic and intestinal ABCG5/G8 in C57BL/6 mice fed with a lithogenic diet (1.25% w/w cholesterol, 0.5% sodium cholate, 16% fat, 2% corn oil), compared to mice fed with a standard rodent diet. Similarly, feeding Wistar rats a 2% cholesterol-enriched diet resulted in increased intestinal expression of ABCG8, as well as liver X receptor α (LXRα), small heterodimer partner (SHP), and sterol regulatory element-binding protein 1c (SREBP-1c), compared to animals receiving the standard diet [169].…”

“…Unfortunately, because of the high heterogeneity of animal models used, experimental methodologies, and diet composition and duration, it is difficult to reach well-defined conclusions. Overall, studies have shown both an increase [28,29,168,169] and a decrease [167,170] in the m-RCT process or RCT molecular players following highcholesterol dietary (from 0.2% to 2% w/w) exposure. On the other hand, the enrichment of diets with phytosterols (0.3-2% w/w) has generated more consistent results, highlighting effects such as reduced intestinal absorption and increased fecal elimination of cholesterol [171,172,181,182].…”

Therapeutic Potential of Danyankang Capsule in High-Fat Diet-Induced Cholelithiasis and Its Impact on Liver FXR Signaling and Gut Microbiota

“…primary instigator for gallbladder stone formation, as emphasized by recent research. 21) It was found that 22,23) TC, TBA, LDL-C levels were significantly increased and HDL-C levels were significantly downregulated in the stone group. In this study, we observed significant increases in TC, TBA, and LDL-C levels in serum, as well as TC content in gallbladder bile, HDL-C levels in serum were significantly reduced in all cases, following 8 weeks of high-fat chow feeding in mice.…”

“…It is plausible that the down-regulation of CYP7A1 and CYP8B1 may be linked to the modulation of PPAR-α or LXR. 37) NF-κB is a nuclear transcription factor responsible for regulating the expression of immunoglobulin K chain in B cells, while TLR4 is a prominent member of the Toll-like receptor family, primarily recognizing microorganisms and initiating inflammatory responses. 38,39) Activation of the TLR4/NF-κB signaling pathway, a critical pathway linked to inflammatory responses, triggers the production of various inflammatory factors such as IL-1β, tumor necrosis factor α (TNF-α), and IL-6.…”

Ursodeoxycholic Acid Use After Bariatric Surgery: Effects on Metabolic and Inflammatory Blood Markers

“…Even though ALP was significantly higher in the UDCA group in all the performed analyses, we believe that the clinical consequence of this degree of elevation (9.40 ± 19.85) is clinically irrelevant. With regard to the lipid spectrum, UDCA has been shown to induce a lower cholesterol saturation index and inhibition of lithogenic genes in mice [28]. Moreover, a recent meta-analysis in PBC patients showed that UDCA treatment is associated with a significant lowering of total cholesterol [2].…”