Fibrates

[aspiringmd1015]

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i think recently someone put a thread up on why fibrates increase cholesterol gall stones, well couldn't find it so I thought I'd put my answer here(not sure if it's right) but apparently insulin simulates hmgcoa reductase, so by that, fibrates induce insulin signaling downstream via PPAR, so that would make sense to me that incr denovo cholesterol synthesis would supersaturated the bile and hence gall stone

 

[Nabin]

i think recently someone put a thread up on why fibrates increase cholesterol gall stones, well couldn't find it so I thought I'd put my answer here(not sure if it's right) but apparently insulin simulates hmgcoa reductase, so by that, fibrates induce insulin signaling downstream via PPAR, so that would make sense to me that incr denovo cholesterol synthesis would supersaturated the bile and hence gall stone

Isn't that effect due to the PPAR-alpha mediated downregulation of 7-alpha-hydroxylase (which converts cholesterol to bile acids)?

 

[aspiringmd1015]

maybe both?

 

[Nabin]

maybe both?

Yeah maybe. It makes sense mechanism wise. I saw some papers and could only find the 7-alpha-hydroxylase mechanism. If you find another one, do mention it.

 

[aspiringmd1015]

i didnt find any papers on it, nor did i see anythign in UW on it, but i saw the mechanism in the biochem section in FA where insulin is stimulating PPAR, and a lightbulb went off in my head, definitely i'd go with your mechanism though, its proven. Also, its not listed but bile acid resins would do the same thing correct? as in cause gallstones.

 

[Nabin]

i didnt find any papers on it, nor did i see anythign in UW on it, but i saw the mechanism in the biochem section in FA where insulin is stimulating PPAR, and a lightbulb went off in my head, definitely i'd go with your mechanism though, its proven. Also, its not listed but bile acid resins would do the same thing correct? as in cause gallstones.

With bile acid binding resins, by binding bile acids in the lumen, there is less bile acids and liver 'tries' to synthesize more cholesterol. This is what I read somewhere. And also bile acids are decreased due to decreased enterohepatic circulation, so the substance that makes cholesterol more soluble is also decreased.

 

[Keto]

Hi..

Here are my notes on fibrates:

Fibrates are PPAR-α agonist. PPAR-α regulate specific transcription factors, that control many aspects of carbohydrate and lipid metabolism - including gene expression of lipoprotein lipase (LPL).

In short: Fibrates induce LPL through PPAR-α.
LPL then promotes the catabolism of VLDL, which increases triglyceride clearance. By breaking down VLDL, LDL production can be stimulated, so an increase of LDL can be observed.

An adverse effect of fibrates is cholelithiasis this is because of the release of free fatty acids by breaking down of VLDL. More fat is excreted through bile, thus there is a higher risk of cholestasis.

As a side note: Other important and clinical relevant adverse effects of fibrates are myositis (in combination of CYP3A4 metabolized statins) and hepatitis. Fibrates also interfere with the metabolism of warfarin ( warfarin should be reduced by 30 percent, if using with fibrates).

Have a great day