PUFAs Cause Fatty Liver (and Reference To Mildronate)

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https://www.researchgate.net/profil...n_capacity/links/02bfe50cf33a43a427000000.pdf

Reduced mitochondrial fatty acid (FA) β-oxidation can cause accumulation of triglyceride in liver, while intake of eicosapentaenoic acid (EPA) has been recommended as a promising novel therapy to decrease hepatic triglyceride content. However, reduced mitochondrial FA β-oxidation also facilitates accumulation of EPA. To investigate the interplay between EPA administration, mitochondrial activity and hepatic triglyceride accumulation, we investigated the effects of EPA administration to carnitine-deficient mice with impaired mitochondrial FA β-oxidation. C57BL/6J mice received a high-fat diet supplemented or not with 3% EPA in the presence or absence of 500 mg mildronate/kg/day for 10 days. Liver mitochondrial and peroxisomal oxidation, lipid classes and FA composition were determined. Histological staining was performed and mRNA level of genes related to lipid metabolism and inflammation in liver and adipose tissue was determined. Levels of pro-inflammatory eicosanoids and cytokines were measured in plasma. The results showed that mildronate treatment decreased hepatic carnitine concentration and mitochondrial FA β-oxidation and induced severe triglyceride accumulation accompanied by elevated systemic inflammation. Surprisingly, inclusion of EPA in the diet exacerbated the mildronate-induced triglyceride accumulation. This was accompanied by a considerable increase of EPA accumulation while decreased total n-3/n-6 ratio in liver. However, inclusion of EPA in the diet attenuated the mildronate-induced mRNA expression of inflammatory genes in adipose tissue. Taken together, dietary supplementation with EPA exacerbated the triglyceride accumulation induced by impaired mitochondrial FA β-oxidation. Thus, further thorough evaluation of the potential risk of EPA supplementation as a therapy for NAFLD associated with impaired mitochondrial FA oxidation is warranted.
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So this is interesting on two levels. One is that it is more mainstream science pointing to the harm from PUFAs.

And it is a warning for anyone messing around too much with mildronate I suppose.
 

paymanz

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Thanks,

Probably its first time I read a bad thing about mildronate!

Maybe in long term it can make this bad effect , or maybe you need to lower your fat intake on mildronate,as much as possible...and maybe cycle it!?
 

Dante

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So, if one has bad fatty acid oxidation capacity then even a minor pufa fat intake would be bad!
So if someone can has successfully transitioned to becoming a fully fledged glucose/sugar oxidator (I don't know a better word) then even a small amount of pufa would cause more damage to liver than what it would have previously ?

Would it also mean that a person taking niacinamide+pufa will get fatty liver sooner than a person taking same amount of pufa without niacinamide.
This would also explain why high doses of niacin is correlated with fatty liver incidences.
 

thyrulian

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So even in a healthy person with superb glucose oxidation & an antioxidant status that fights full force against nasties like lipid peroxidation, you still get ***t like this = PUFAs are always bad news.
 

jitsmonkey

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mildronate seems to mess with creatine metabolism...anyone know much about that?
this would certainly incriminate someone on a high fat, particularly high pufa diet.
It would seem to offer little or no problem to those eating a low fat / low pufa diet.

Mildronate is an ischemic heart disease drug when used on label. Studies though sparse are encouraging.
I can't imagine those heart patients who responded favorably showed similar difficulties as seen in this study and the drug still being seen favorably.
I also can't imagine they'd be the healthiest of folks, they'd likely be rife with pufa damage and endogenous pufa excess
all interesting considerations
 

Wagner83

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Interesting I wonder if the issues with mildronate would be seen with niacinamide too.
 

GAF

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My mildronate experience so far tells me that my pufa consumption goes way down while taking it so the problem noted may not be a real world issue
 

ecstatichamster

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http://pharmacologyonline.silae.it/files/archives/2006/vol1/01_Sjakste.pdf

The main mechanism of action of Mildronate is based on carnitine biosynthesis inhibition aimed to prevent accumulation of cytotoxic intermediate products of fatty acid beta- oxidation in ischemic tissues and to block this highly oxygen-consuming process. Alternatively the drug acts via stimulation of the nitric oxide production in the vascular endothelium through a modification of the γ-butyrobetaine and γ-butyrobetaine ester pools. The present review will summarize data on the Mildronate on different indications of the drug and its mechanisms of action.
 
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