9 replies to this topic

[Brett Black]

Proc Natl Acad Sci U S A. 2012 Feb 13. [Epub ahead of print]

Inhibitory effect of dietary lipids on chaperone-mediated autophagy.

Rodriguez-Navarro JA, Kaushik S, Koga H, Dall'armi C, Shui G, Wenk MR, Di Paolo
G, Cuervo AM.

Department of Developmental and Molecular Biology, Institute for Aging Studies,
Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx,
NY 10461.

Cytosolic proteins can be selectively delivered to lysosomes for degradation
through a type of autophagy known as chaperone-mediated autophagy (CMA). CMA
contributes to intracellular quality control and to the cellular response to
stress. Compromised CMA has been described in aging and in different age-related
disorders. CMA substrates cross the lysosomal membrane through a translocation
complex; consequently, changes in the properties of the lysosomal membrane should
have a marked impact on CMA activity. In this work, we have analyzed the impact
that dietary intake of lipids has on CMA activity. We have found that chronic
exposure to a high-fat diet or acute exposure to a cholesterol-enriched diet both
have an inhibitory effect on CMA. Lysosomes from livers of lipid-challenged mice
had a marked decrease in the levels of the CMA receptor, the lysosome-associated
membrane protein type 2A, because of loss of its stability at the lysosomal
membrane. This accelerated degradation of lysosome-associated membrane protein
type 2A, also described as the mechanism that determines the decline in CMA
activity with age, results from its increased mobilization to specific lipid
regions at the lysosomal membrane. Comparative lipidomic analyses revealed
qualitative and quantitative changes in the lipid composition of the lysosomal
membrane of the lipid-challenged animals that resemble those observed with age.
Our findings identify a previously unknown negative impact of high dietary lipid
intake on CMA and underscore the importance of diet composition on CMA
malfunction in aging.

PMID: 22331875 [PubMed - as supplied by publisher]

http://www.ncbi.nlm....pubmed/22331875

[niner]

Thanks for that, Brett. Seems like a big negative for hyperlipid diets. I'd guess that the mice were fed a lot more fat than they are evolved for, so I still wonder what exactly it means for humans, but CMA is not something you want to mess up. I've never been a fan of hyperlipid diets, but to me this is just another nail in their coffin.

[yoyo]

I can't access the fulltext, but I would be suspicious it wasn't isocaloric. Can anyone confirm?

[Brett Black]

I can't access the fulltext, but I would be suspicious it wasn't isocaloric. Can anyone confirm?

It's a long, dense and technical paper that I have trouble wading through, but I could find no reference to either control or monitoring of calorie intake. If the mice were fed ad-libitum that could be a serious weakness given the tendency for high fat diets to induce obesity in mice and the known modulation of autophagy by calorie intake.

[niner]

but I could find no reference to either control or monitoring of calorie intake.

Wouldn't they always weigh the food in a study like this?

[brunotto]

<sub>Statins are widely used to treat hypercholesterolemia, but they are associated with muscle-related adverse events, by as yet, inadequately resolved mechanisms. In this study, we report that statins induced autophagy in cultured human rhabdomyosarcoma A204 cells. Potency differed widely among the statins: cerivastatin induced autophagy at 0.1 μM, simvastatin at 10 μM but none was induced by pravastatin. Addition of mevalonate, but not cholesterol, blocked induction of autophagy by cerivastatin, suggesting that this induction is dependent on modulation of isoprenoid metabolic pathways. The statin-induced autophagy was not observed in other types of cells, such as human hepatoma HepG2 or embryonic kidney HEK293 cells. Muscle-specific abortive induction of autophagy by hydrophobic statins is a possible mechanism for statin-induced muscle-related side effects.

http://www.sciencedi...006291X07028240</sub>

[brunotto]

They differ primarily in their degree of oil solubility. The more oil-soluble (lipophilic) is the statin, the more easily it can cross the blood-brain-barrier and directly affect neurons and their support tissues.
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The blood-brain-barrier prevents cholesterol and other fats in the bloodstream from reaching the neurons. In consequence the neurons or their support tissues (glia, astrocytes) must synthesize the cholesterol required for neuron structures. If this synthesis is inhibited by statin use, the neurons might be impaired thereby in some vital function. This is in fact the argument advanced by some against statin use. It may be behind the rare memory-loss side-effects reported in statin use.
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There is even a remarkable statistical study where the incidence of dementia and parkinsonism was seen to be reduced by half with simvastatin and much less with atorvastatin or lovastatin.
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In fact cholesterol depletion by lipophilic statins is a known inducer of autophagy⁴⁶ and this may be the mechanism by which it reduces dementia and parkinsonism, clearing the mis-folded protein aggregates associated with these conditions. In the near future statins may be prescribed for AD and PD even where cholesterol levels are normal.
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It is not too surprising that blocking cholesterol synthesis seems to promote autophagy. When cell membranes are recycled, the cholesterol they contain is made available for new membrane synthesis in the same way as amino acids are made available for new protein synthesis. Perhaps cycling statins could be as effective as cycling proteins in promoting autophagy. We may never know since statins are coming off their patents and there is little incentive to do the necessary studies. Further statins have some problems in crossing the blood-brain barrier and would likely promote autophagy less in the CNS than in the rest of the body, the exact opposite of what is desired to restrain the development of neurodegenerative diseases.


http://proteincyclin...3nmvrwklbxs-19/

Pravastatin is not fat soluble so it spare the brain... but for AD or PD better fat soluble stains like simvastain inducing autophagy inside the brain.

Edited by brunotto, 17 March 2012 - 12:53 PM.

[Mind]

I can't access the fulltext, but I would be suspicious it wasn't isocaloric. Can anyone confirm?

It's a long, dense and technical paper that I have trouble wading through, but I could find no reference to either control or monitoring of calorie intake. If the mice were fed ad-libitum that could be a serious weakness given the tendency for high fat diets to induce obesity in mice and the known modulation of autophagy by calorie intake.

This is a key weakness, total calories. CR and fasting upregulate CMA. Well known.

Also, results from herbivores don't necessarily translate to omnivores.

I am not defending high-fat diets, just pointing out the weaknesses of this study.

Fat is an essential nutrient for humans. Even Dr. Weil (an illogical appeal to authority, I know) suggests up to 30% of calories from fat.

[Brett Black]

Fat is an essential nutrient for humans.

Sure, but current essential nutrient requirements are just those that are capable of sustaining an average lifespan and healthspan, and that's not what I'm looking for. I want "ideal" nutritional requirements that will allow better than average lifespan and healthspan.

Methionine is an essential nutrient for rodents, yet frank "deficiency" increases their lifespan. Rapamycin is not an essential nutrient for rodents, yet addition of rapamycin to the diet increases their lifespan.

Even Dr. Weil (an illogical appeal to authority, I know) suggests up to 30% of calories from fat.

I'm not arguing for a low fat diet, but even those on a ~10% total fat diet, like Ornish, can apparently meet essential fat needs, so anything beyond that level(and perhaps much less) could be defined as non-essential fat intake.

[Chupo]

Just keep your carbs low enough to be in ketosis. Ketone bodies stimulate chaperone-mediated autophagy.

http://www.jbc.org/c...0/27/25864.long