tag:blogger.com,1999:blog-36840063.post908255692392263191..comments2024-03-27T22:57:00.742+00:00Comments on Hyperlipid: Protons: FastingPeterhttp://www.blogger.com/profile/14527788116058656094noreply@blogger.comBlogger10125tag:blogger.com,1999:blog-36840063.post-32298306725276843582012-08-13T01:04:48.877+00:002012-08-13T01:04:48.877+00:00Is this the connection between selenium supplement...Is this the connection between selenium supplements and increased diabetes risk (nearly doubled in this study; <a href="http://naldc.nal.usda.gov/download/46763/PDF" rel="nofollow">http://naldc.nal.usda.gov/download/46763/PDF</a>)<br />Dietary Se seems to be protective if anything. Which may be a matter of timing and adaptation.Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-36840063.post-65137105945819538252012-08-09T23:20:21.376+00:002012-08-09T23:20:21.376+00:00If you only read free radical and aging theory, it...If you only read free radical and aging theory, it's easy to assume that ROS just diffuse everywhere until they hit an antioxidant, maybe a receptor, or an oxidizable protein or fat, which they damage.<br />It's hard to know how they move, but I think it likely that most are targetted in various ways.<br />e.g., Catalase is very efficient, but it cannot be everywhere. High efficiency is redundant if ROS are also going everywhere else.<br />A batter with a high hit rate needs a reliable pitcher.<br />It more likely that SOD and catalase are coupled in some way.<br />Similarly, GSH must be delivered to GPx; it cannot just wander over at diffusion rates.<br />I predict (with admittedly no evidence) that the majority of ROS are emitted in the direction of their proper targets or are guided along currents by weak (e.g. non-covalent bond type) forces.Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-36840063.post-72166943668264133622012-08-06T23:38:19.617+00:002012-08-06T23:38:19.617+00:00This paper is a review of papers on HCV mitochondr...This paper is a review of papers on HCV mitochondrial manipulation. Page 7 mentions reducing equivalents and ROS.<br />Also the paper is around PPARs and PPAR alpha is upregulated in carb restriction, inhibited by HCV core protein.<br />"The combination of these possible effects [Complex 1 inhibition with concomitant complex 4 inhibition by Ca+] would result in an over-load of harmful reducing equivalents throughout the respiratory chain complexes and in an extra-production of ROS with respect to their basal level [60,61]."<br /><a href="www.hindawi.com/journals/ppar/aip/605302.pdf" rel="nofollow">www.hindawi.com/journals/ppar/aip/605302.pdf</a><br /><br />Gotta love the Italians; they always seem to be streets ahead in HCV research.Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-36840063.post-77722110958496311032012-08-06T22:16:38.491+00:002012-08-06T22:16:38.491+00:00Ah, perhaps the JNK is the circuit that conveys RO...Ah, perhaps the JNK is the circuit that conveys ROS complex 1 messages from the mitochonria to the nucleus.<br />Interestingly, this seems to be much the same circuit that cortisol uses.<br />I find the analogue circuitry metaphor to be the best way to get my head around transcription factors.<br />The nucleotides are digital memory, the proteins are analogue circuitry.<br /><br />"Inflammatory signals, changes in levels of reactive oxygen species, ultraviolet radiation, protein synthesis inhibitors, and a variety of stress stimuli can activate JNK. One way this activation may occur is through disruption of the conformation of sensitive protein phosphatase enzymes; specific phosphatases normally inhibit the activity of JNK itself and the activity of proteins linked to JNK activation.<br />JNK, by phosphorylation, modifies the activity of numerous proteins that reside at the mitochondria or act in the nucleus." Wikipedia.<br /><br />I suspect that it's not actually necessary to know any of this, and that genomics in biochemistry textbooks is just displacing the more useful clinical and physiological detail you find in older editions.<br />But Fox01, JNK and the gang do make for handy search terms.Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-36840063.post-19662057817325552682012-08-06T01:34:07.770+00:002012-08-06T01:34:07.770+00:00Hi Peter, great post.
“All tissues which can becom...Hi Peter, great post.<br />“All tissues which can become insulin resistant should do so under these conditions.”<br />I’m guessing this is MOST important in the early stages of starvation when ketones are too low to support the brain. And you’re saying this is related to the spike in insulin resistance after only 3 days of overfeeding: both are caused by superoxide produced as a byproduct from palmitate oxidation. Right?<br />Thanks, BillBillhttps://www.blogger.com/profile/05022558754270362782noreply@blogger.comtag:blogger.com,1999:blog-36840063.post-31428455659703534532012-08-06T00:57:03.738+00:002012-08-06T00:57:03.738+00:00Here's the rest of the complex 1 ROS => Fox...Here's the rest of the complex 1 ROS => Fox01 pathway:<br />From <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165828/" rel="nofollow">the HCV model of IR</a>.<br />But as far as I can tell the fructose + high carb model is the same at the transcription end - and maybe the complex 1 end is substantitively the same.<br />In a Lustig sort of way, of course; "fructose is exactly the same metabolically as hepatitis C".<br />I don't think I'm there quite yet.<br /><br /><br /><br />HCV infection induced JNK activation via increased mitochondrial ROS production, resulting in decreased FoxO1 phosphorylation, FoxO1 nuclear accumulation, and, eventually, increased glucose production. We also found that HCV NS5A mediated increased ROS production and JNK activation, which is directly linked with the FoxO1-dependent increased gluconeogenesis.Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-36840063.post-4599607620801855032012-08-05T21:22:29.227+00:002012-08-05T21:22:29.227+00:00And if the ROS => Nucleus => decreased phosp...And if the ROS => Nucleus => decreased phospholylation of Fox01 => retention in nuleus => increased activity of Fox 01 => gluconeogenesis pathway in hepatocytes (as seen in HCV and diabetes) works in the fasting state, we also have the source of that extra glucose the brain needs.<br />Ketoacids from gluconeogenic amino acids and lactate, and glycerol, being the main substrates.<br /><br />How do the ROS get from the mitochondria to the nucleus?<br /><br />Complex 1 and ROS, HCV model<br /><a href="http://www.ncbi.nlm.nih.gov/pubmed/16150732" rel="nofollow">http://www.ncbi.nlm.nih.gov/pubmed/16150732</a><br /> "Liver mitochondria from transgenic mice expressing the HCV proteins core, E1 and E2 demonstrated oxidation of the glutathione pool and a decrease in NADPH content. In addition, there was reduced activity of electron transport complex I, and increased ROS production from complex I substrates. There were no abnormalities observed in complex II or complex III function. Incubation of control mitochondria in vitro with recombinant core protein also caused glutathione oxidation, selective complex I inhibition, and increased ROS production. Proteinase K digestion of either transgenic mitochondria or control mitochondria incubated with core protein showed that core protein associates strongly with mitochondria, remains associated with the outer membrane, and is not taken up across the outer membrane. Core protein also increased Ca(2+) uptake into isolated mitochondria. These results suggest that interaction of core protein with mitochondria and subsequent oxidation of the glutathione pool and complex I inhibition may be an important cause of the oxidative stress seen in chronic hepatitis C."<br /><br />If, as it appears, this sort of thing is also done by other viruses, the idea of pathogenic factors playing a role in the obesity epidemic isn't so far out.<br />In my day (60s, 70s) we ate junk food, sugar, and to excess. People got very unhealthy and dropped dead of heart attacks, yet modern type of obesity was quite rare. There was only one fat kid per school. <br /><a href="http://ajpregu.physiology.org/content/290/1/R188.short" rel="nofollow">http://ajpregu.physiology.org/content/290/1/R188.short</a><br />Viral obesity.<br /><br />There's also been a correlation between the growing size of vaccination schedules and growing size of people. It would be good to see a study looking at whether total number of shots correlates with BMI or DM2 (not just vaccinated vs unvaccinated).Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-36840063.post-37452888415556368222012-08-05T14:36:24.766+00:002012-08-05T14:36:24.766+00:00aelephant, Yes: Lactate to pyruvate to oxphos. Dir...aelephant, Yes: Lactate to pyruvate to oxphos. Direct fuel injection, as close as you can get. Bugger glycolysis in the neurons themselves. I think it's probably correct. Now does insulin influence the PDH complex in the neurones as it does in other tissues? And does neuronal lipid accumulation affect this? So many questions.<br /><br />PeterPeterhttps://www.blogger.com/profile/14527788116058656094noreply@blogger.comtag:blogger.com,1999:blog-36840063.post-32356111280271725392012-08-05T04:47:15.440+00:002012-08-05T04:47:15.440+00:00This is a bit off topic, but with all of the talk ...This is a bit off topic, but with all of the talk about the brain needing Glucose during starvation, I was curious if you've heard about the hypothesis that Lactate is preferentially used as a fuel in the brain? <br /><br />http://en.wikipedia.org/wiki/Lactic_acid#Brain_metabolismaelephanthttps://www.blogger.com/profile/15337430274390797972noreply@blogger.comtag:blogger.com,1999:blog-36840063.post-21801058281338280912012-08-04T23:04:10.912+00:002012-08-04T23:04:10.912+00:00I appreciate this approach of thinking about IR as...I appreciate this approach of thinking about IR as a natural response by the body when necessary, rather than a disorder. I have similarly seen obesity discussed in terms of a defense mechanism. Even if both these premises turn out to be false (and I doubt they will) I think it useful to "shake up" dogmatic thinking in this way and examine what has been taken as established "fact" from another angle. Perhaps this is how science should be done?FrankGhttps://www.blogger.com/profile/01980497914756341565noreply@blogger.com