Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance
Evidence suggests that caffeine (CF) reduces cardiovascular disease (CVD) risk. However, the mechanism by which this occurs has not yet been uncovered. Here, we investigated the effect of CF on the expression of two bona fide regulators of circulating low-density lipoprotein cholesterol (LDLc) levels; the proprotein convertase subtilisin/kexin type 9 (PCSK9) and the low-density lipoprotein receptor (LDLR). Following the observation that CF reduced circulating PCSK9 levels and increased hepatic LDLR expression, additional CF-derived analogs with increased potency for PCSK9 inhibition compared to CF itself were developed. The PCSK9-lowering effect of CF was subsequently confirmed in a cohort of healthy volunteers. Mechanistically, we demonstrate that CF increases hepatic endoplasmic reticulum (ER) Ca2+ levels to block transcriptional activation of the sterol regulatory element-binding protein 2 (SREBP2) responsible for the regulation of PCSK9, thereby increasing the expression of the LDLR and clearance of LDLc. Our findings highlight ER Ca2+ as a master regulator of cholesterol metabolism and identify a mechanism by which CF may protect against CVD.
https://nature.com/articles/s41467-022-28240-9
How to Make Statins Work Better Against Cancer?
Reduce cancer cells resistance to Statins with the help of the FDA approved drug Dipyridamole
Statins inhibit the rate-limiting enzyme of the mevalonate (MVA) pathway called HMG-CoA reductase (HMGCR). This is also the mechanism through which it is believed that statins kill cancer. However, it seems that most cells have a way to overcome the HMGCR inhibition with the help of the sterol regulatory element-binding protein 2 (SREBP2). Using Dipyridamole, a FDA approved drug, will block SREBP2 activation and thus, maintain the effectiveness of Statins (Ref.1, Ref.2).
https://cancertreatmentsresearch.com/cholesterol-lowering-statin-drugs-to-fight-cancer
Coffee is medicine! 🙂
In breast cancer:
"Moderate (2–4 cups/day) to high (≥5 cups/day) coffee intake was associated with smaller invasive primary tumors (Ptrend = 0.013) and lower proportion of ER+ tumors (Ptrend = 0.018), compared with patients with low consumption (≤1 cup/day). Moderate to high consumption was associated with lower risk for breast cancer events in tamoxifen-treated patients with ER+ tumors (adjusted HR, 0.51; 95% confidence interval, 0.26–0.97). Caffeine and caffeic acid suppressed the growth of ER+ (P ≤ 0.01) and ER− (P ≤ 0.03) cells. Caffeine significantly reduced ER and cyclin D1 abundance in ER+ cells. Caffeine also reduced the insulin-like growth factor-I receptor (IGFIR) and pAkt levels in both ER+ and ER− cells. Together, these effects resulted in impaired cell-cycle progression and enhanced cell death."
In breast cancer:
"Moderate (2–4 cups/day) to high (≥5 cups/day) coffee intake was associated with smaller invasive primary tumors (Ptrend = 0.013) and lower proportion of ER+ tumors (Ptrend = 0.018), compared with patients with low consumption (≤1 cup/day). Moderate to high consumption was associated with lower risk for breast cancer events in tamoxifen-treated patients with ER+ tumors (adjusted HR, 0.51; 95% confidence interval, 0.26–0.97). Caffeine and caffeic acid suppressed the growth of ER+ (P ≤ 0.01) and ER− (P ≤ 0.03) cells. Caffeine significantly reduced ER and cyclin D1 abundance in ER+ cells. Caffeine also reduced the insulin-like growth factor-I receptor (IGFIR) and pAkt levels in both ER+ and ER− cells. Together, these effects resulted in impaired cell-cycle progression and enhanced cell death."
Interestingly, estrogen causes water retention and coffee is a natural diuretic. Tumor-bearing tissues often have a significantly higher water content than normal tissues.
Interestingly, estrogen causes water retention and coffee is a natural diuretic. Tumor-bearing tissues often have a significantly higher water content than normal tissues.
Serotonin acts like estrogen and raises intracellular pH. I speculate that estrogen and serotonin receptor antagonists actually decrease intracellular water and thus acidify the tumor.
