Study Results Suggest Rosuvastatin, Cholesin Combination Therapy May Improve Cholesterol Homeostasis

Cholesin, a cholesterol-induced gut hormone, regulates cholesterol metabolism, according to a study published in Cell. The findings suggest the use of the hormone as a potential monotherapy or combination treatment with rosuvastatin (Crestor; AstraZeneca Pharmaceuticals LP) to encourage cholesterol homeostasis, combatting the risk of developing conditions such as hypercholesterolemia or atherosclerotic cardiovascular disease (ASCVD).¹

The results suggest the potential use of cholesin as a complementary agent to statins to enhance their cholesterol-lowering capabilities. Image Credit: © Grispb - stock.adobe.com

Cholesterol is a necessary substance for cell creation in the body; however, high levels are risk factors for the development of various cardiovascular diseases (CVDs) and complications. Various factors can increase risk including smoking, obesity, genetics, or poor diet and lack of physical activity.²

Cholesterol homeostasis is a vital function for proper cellular and systemic functions, as well as balancing levels of the substance to prevent the onset of CVDs. The bidirectional coordination between cholesterol absorption in the intestine de novo cholesterol synthesis in the liver is crucial for maintaining cholesterol homeostasis; however, the mechanisms opposing regulation of these necessary processes remains misunderstood.^1,3

Researchers from the Tsinghua-Peking Center for Life Sciences at Tsinghua University in Beijing, China, conducted a fasting-refeeding study and analyzed plasma proteins from mice that fasted for 16 hours and fed for 1 hour on a Western or regular diet. Through silver staining, they found the 23 kDa protein band in the group of mice refed with the Western diet, which was later identified as the human protein C7orf50, or cholesin.³

Cholesin is a hormone found in the gut that is secreted from the intestine in response to cholesterol absorption. It binds to the orphan GPR146 protein, thereby inhibiting PKA signaling and suppressing SREBP2-controlled cholesterol synthesis in the liver, thereby reducing circulating cholesterol levels. In the model, the researchers demonstrated that cholesin secreted in the plasma was highly expressed in the intestine and colons and mice and humans.^1,3

In humans, as plasma cholesin levels increased, plasma total cholesterol, triglycerides, apolipoprotein B (APOB), and LDL-C levels decreased; however, no association with high-density lipoprotein cholesterol was detected. To support these relationships, the researchers observed that mice lacking cholesin produced substantially elevated plasma, hepatic cholesterol, triglyceride levels following a Western diet feeding.³

Next, they needed to understand the mechanism underlying cholesin’s ability to mediate its effect on hepatic cholesterol. Through comparing the results of flow cytometry of different cell lines based on their ability to bind to cholesin, the research team identified the role of GPR146, a protein reported to regulate circulating cholesterol. In tissue samples from the transgenic mice, it was reported that cholesin’s binding affinity decreased in the absence of Gpr146 signaling.³

The summation of these findings led to an investigation of the atheroprotective potential of cholesin during hypercholesterolemia and ASCVD. The researchers evaluated cholesin as a monotherapy or in combination with rosuvastatin in transgenic mice lacking low-density lipoprotein receptor, a well-established model of ASCVD.³

The data showed that cholesin as a monotherapy significantly lowered plasma cholesterol and expression of hepatic cholesterogenic genes. Rosuvastatin as a single agent treatment also decreased plasma cholesterol but upregulated the expression of cholesterogenic genes.³

When used in combination, cholesin overrode the rovustatin-induced increase of cholesterogenic gene expression to allow for the improved inhibitory effect on plasma cholesterol and atherosclerotic lesions; additionally, the treatment decreased body weight gain, lipid accumulation, and liver inflammation, as well as lowered plasma triglyceride levels.³

The results suggest the potential use of cholesin as a complementary agent to statins to enhance their cholesterol-lowering capabilities. Continued research is needed to understand the long-term benefits, safety, and efficacy of cholesin, as well as investigate its use in combination with other statin agents.

REFERENCES

1. Hu X, Chen F, Jia L, et al. A gut-derived hormone regulates cholesterol metabolism. Cell. March 18, 2024. doi:10.1016/j.cell.2024.02.024

2. High cholesterol. Mayo Clinic. January 11, 2023. Accessed October 3, 2024. https://www.mayoclinic.org/diseases-conditions/high-blood-cholesterol/symptoms-causes/syc-20350800

3. Peter U Amadi, Da-Wei Zhang. Cholesin, a new hormone bridges intestinal cholesterol absorption and hepatic synthesis. Life Metabolism, June 7, 2024. doi:10.1093/lifemeta/loae024