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38. Matsuyama H, Sato K, Nakamura Y, Suzuki K, Akiba Y. Modulation of regulatory factors involved in cholesterol metabolism in response to feeding of pravastatin- or cholesterol-supplemented diet in chickens. 2005;1734:136-142
Low-density lipoprotein - Wikipedia
All animal studies were approved by the Institutional Animal Care and Use Committee (IACUC) at Merck Research Laboratories. A transgenic mouse model expressing the human CETP transgene and a single allele copy of the LDL-receptor (CETP[LDLR+/-]) was utilized. 12-week old male mice were treated IV with indicated doses of 1B20 and serum samples were collected at indicated time points for measurements of LDL-C, total and free PCSK9, and 1B20 levels. Serum samples were treated with lipase inhibitors and protease inhibitors (Sigma), stored at 4°C and assayed within 7 days of sample collection. LDL-C was measured with LDL Direct Select Cholesterol Reagent ( Diagnostics). Liver samples were flash frozen in liquid nitrogen and stored at -80oC until analysis.
While I’ve not worked out all the details regarding the pathways. I can say that I think it is not entirely supply-driven, such as a lipolysis and glycerolneogenesis combination influencing at the liver to higher VLDL synthesis/recirculation. Rather, there seems to be a systemic, demand-driven process, which better explains my own data and it’s tight homeostasis.
Effects of Human Growth Hormone in Men over 60 …
Messenger RNA expression of SREBP-regulated key genes in cholesterol and fatty acid synthesis pathways was reduced in human primary hepatocytes comparing treatment with 1B20 + simvastatin versus simvastatin alone.
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As part of the primary hepatocytes study, we measured PCSK9 and LDLR mRNA to evaluate the possible effect of 1B20 treatment on SREBP tone. As shown in Figure , simvastatin treatment induced increases in PCSK9 and LDLR mRNAs, and 1B20 treatment partially reversed this induction in a dose-dependent manner. This is consistent with the notion that PCSK9 inhibition would lead to increased cellular cholesterol uptake and decreased SREBP tone, and also is in agreement with reductions of PCSK9/LDLR mRNA levels in the livers of mice treated with 1B20. To further evaluate the transcriptional effect of 1B20, mRNA levels of genes representing major lipid metabolism pathways were measured. As shown in Table , comparing 1B20 + simvastatin combination versus simvastatin alone, the mRNA levels of key genes in both cholesterol and fatty acid synthesis pathways were reduced, consistent with a reduced SREBP activity.
The Estimated Number of Stars in the Universe Just …
What effect does activated AMPK have on the cell? Active AMPK activates liver glycolysis (byphosphorylating phosphofructokinase 2 which forms F2,6-BP, an activator of PFK) and inhibits by phosphorylation enzymes inovled in fatty acid synthesis (acetyl-CoA carboxylase), glycogen synthesis (glycogen synthase) and cholesterol synthesis (HMG-CoA reductase). Yeast AMPK has recently been shown to be also controlled by acetylation of the equivalent beta subunit (Sip2). Acetylation increases its interaction with the alpha catalytic subunit (Snf1) which decreases its kinase activity. This decreases phosphorylation of downstream kinases (including an analog of Akt1 called Sch9) which slows growth and increases longevity. Normal aging is associated with decreased acetylation of Sip2.
06.01.2018 · Lanosterol → Cholesterol; Synthesis ..
Sub-cutaneous (SC) administration is the preferred route of delivery in humans. To test the feasibility and aid SC dose selection in humans, a study was conducted in healthy rhesus monkeys to evaluate PK, PD (pharmacodynamics) and TE (target engagement) of 1B20 following a single SC or IV dose of 1 and 10 mpk of 1B20. As shown in Figure , at 1 mpk, SC and IV dosing led to similar serum 1B20 levels. At 10 mpk, SC dosing of 1B20 led to higher day 2-7 circulating levels of 1B20, possibly due to the extended release of 1B20 into circulation after SC dosing. Consistent with the PK profile, at 1 mpk, SC and IV dosing led to similar time courses of % LDL changes, while at 10 mpk, SC dosing led to longer duration of LDL reduction with LDL returning to baseline around day 28, demonstrating a strong PK-PD relationship (Figure ). At 1 mpk SC and IV dosing, % TE returned to baseline around day 15, which is consistent with the time course of LDL changes; at 10 mpk SC and IV dosing, %TE returned to baseline around day 28, and is also consistent with the LDL changes, suggesting a good TE-PD correlation. Overall, these data demonstrate a PK-PD-TE correlation. Additionally, similar to what was seen in the mouse study, 1B20 treatment promoted a transient increase in total PCSK9 levels (2-3 fold), which returned to baseline levels during the study (Figure ). In summary, both IV and SC dosing of 1B20 induced robust LDL-C lowering in healthy, normocholesterolemic monkeys, and the preferred route of administration is SC, which makes it amenable for self-injections in humans.