"I Have Liver Issues And I Am Not Making Progress"

[haidut]

View attachment 7005
Time to include B5 antagonist in Energin.

I would not want to get people deficient in B5 but it would be interesting to see what the symptoms of deficiency are. Can you do a quick search? If deficiency causes increased oxygen consumption and uncoupling then I am all game

 

[Amazoniac]

I would not want to get people deficient in B5 but it would be interesting to see what the symptoms of deficiency are. Can you do a quick search? If deficiency causes increased oxygen consumption and uncoupling then I am all game

The funny part is that I'm actually considering searching for that..

 

[Amazoniac]

https://www.jstage.jst.go.jp/article/jnsv/59/6/59_509/_pdf

PaA deficiency elicits the inhibition of the reaction of pyruvic acid dehydrogenase, which leads the accumulation of pyruvic acid.

 

[Amazoniac]

http://www.jbc.org/content/175/2/515.full.pdf

"These preliminary findings of a reduced pyruvate utilization in tissues from pantothenic acid-deficient rats were in good agreement with the report of Pilgrim, Axelrod, Diokine, and Elvehjem (8) that pyruvate failed to stimulate oxygen uptake in homogenates of liver from pantothenic acid-deficient rats. The fact that this reduced pyruvate utilization occurred first when the tissues had become depleted of coenzyme A was of great interest and prompted further experimentation."

"Decreases of 50 to 70 per cent in the tissues of deficient rats and ducks were found in this study.
Associated with this decrease in the coenzyme A content of heart and liver in both species there is a decrease in the ability of these tissues to metabolize pyruvic acid. The conversion of pyruvate to products other than lactate is sharply curtailed in liver slices from deficient ducks and is restored to approximately normal by the injection of pantothenic acid 1 to 2 hours before sacrifice of the birds. The injection of pantothenate also restores the coenzyme A levels to normal."

 

[Amazoniac]

Dietary Broccoli Lessens Development of Fatty Liver and Liver Cancer in Mice Given Diethylnitrosamine and Fed a Western or Control Diet
"HTGs [hepatic triglycerides, responsible for the accumulation] mainly derive from circulating nonesterified fatty acids (NEFAs; 60%), whereas minor sources are de novo lipogenesis (25%) and dietary fat (15%) (39)."

 

[Amazoniac]

Trimethylamine N-Oxide: The Good, the Bad and the Unknown

 

[Amazoniac]

3:51 - "if you accumulate fat in your liver cells, that in itself is associated with metabolic dysregulation and cardiovascular disease. And since the liver is the metabolic hub of the body, the central organ of detoxification, playing so many central roles, there are probably many reasons for why fat accumulation in liver would be associated with disease risk." "if you look at liver cells under a microscope, when they've accumulated triglycerides, the nuclei of those cells are flattened. That's because the triglycerides take up so much room, but there's not even room left for the nuclei of those cells. Imagine what that does to your glycogen storage. Those are the cells that you stored glycogen in. So if the fat is taking up so much room in the hepatocytes that it's smooshing and flattening the nuclei, you can bet your bottom dollar that that cell doesn't have room for glycogen storage. And if you are decreasing your ability to store glycogen, how are you going to maintain stable blood sugar through the course of the day and overnight, when your primary means of maintaining stable blood sugar in between meals is to access your hepatic glycogen?"

7:00 - "The more fat you have circulating in the blood, the more exposure the liver has to that fat."

7:28 - "out of [dietary fat, fructose, and ethanol], dietary fat is much more important simply because de novo lipogenesis, the synthesis of fat from nonfat precursors is a minor pathway in humans. De novo lipogenesis is increased threefold in people who have fatty liver disease, but its contribution to the hepatic fat pool is estimated to increase from about 5 to 15%. So it's still minor compared to dietary fat and circulating fat that's entering the liver because it's not being stored in adipose tissue [insulin resistance cycle]."

10:42 - Lipid peroxidation leads to the oxidative destruction of hepatic ApoB [responsible for exporting fats from the liver]. Iron chelator or vit E, both normalize the inflammation that occurs when PUFA is present. They also almost normalize the secretion of the exporting protein in the presence of PUFA. "Oxidative stress in the liver causes a massive decrement in ApoB secretion."

13:15 - Coconut oil abolishes inflammation as if animals weren't deficient (choline and methionine), quite remarkable. It also spares glutathione, again, as if animals weren't deficient. PUFA had the opposite effect.

Coconut Oil
The unsaturated oils in some cooked foods become rancid in just a few hours, even at refrigerator temperatures, and are responsible for the stale taste of left-over foods. (Eating slightly stale food isn't particularly harmful, since the same oils, even when eaten absolutely fresh, will oxidize at a much higher rate once they are in the body, where they are heated and thoroughly mixed with an abundance of oxygen.) Coconut oil that has been kept at room temperature for a year has been tested for rancidity, and showed no evidence of it. Since we would expect the small percentage of unsaturated oils naturally contained in coconut oil to become rancid, it seems that the other (saturated) oils have an antioxidative effect: I suspect that the dilution keeps the unstable unsaturated fat molecules spatially separated from each other, so they can't interact in the destructive chain reactions that occur in other oils. To interrupt chain-reactions of oxidation is one of the functions of antioxidants, and it is possible that a sufficient quantity of coconut oil in the body has this function. It is well established that dietary coconut oil reduces our need for vitamin E, but I think its antioxidant role is more general than that, and that it has both direct and indirect antioxidant activities.​

15:35 - A low-fat diet is similar to coconut oil when it comes to inflammation. Ironically, consuming a low-fat diet rendered even worse accumulation of fat in the liver in comparison to coconut oil. However I opened the study a long time ago, and if I remember correctly, what they refer to as low-fat is questionable (and it was actually less PUFA than normal). So, all dietary fats tend to accumulate, including coconut oil and cause the mentioned problems at the begining, regardless of how safe they are. On the bigger picture, it can have a slightly negative effect. If you have too much stored PUFA, I would go the coconut oil route, with plenty of it. Rayzord mentioned that saturated fats can be curative in liver problems: if it's already turned to burning fats, it's better that you supply saturated ones to protect the organ anyway. But if you don't have excess of PUFA, it's better to go the low-fat route, and of course prioritizing coconut oil or butter as fats, just not so in great amounts. In both cases some vit E and iron chelators are probably helpful as well.

17:08 - Green tea mimics fasting/caloric restriction. Since it all comes down to excess of what you can handle, minimizing energy intake will reduce the damage. There are many discussions on the forum about fasting defattening organs. It's stressful, but possibly less than the current overloaded state.

 

[Amazoniac]

Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss
"Resistance exercise provides an alternative to aerobic exercise; it improves muscular strength, muscle mass and metabolic control, safely and effectively, in vulnerable populations independent of weight loss.16 It places less of a demand on the cardiorespiratory system and may therefore be accessible to more patients.17 All participants completed the 8-week programme, showing good adherence and tolerance."

Effect of resistance training on non-alcoholic fatty-liver disease a randomized-clinical trial
"Professional societies recommend ≥ 30 min of moderate-intensity aerobic PA [physical activity] on most, and preferably all, days of the week, or vigorous-intensity PA ≥ 3 times per week for ≥ 20 min each time. However, only 27.7% United States adults meet recommended levels of either moderate or vigorous physical activity, whereas 29.2% report no regular PA outside of their work[68,69]. Moreover, the prevalence of physically active adults among patients with diabetes is lower than in those without diabetes[70] and they are less likely to meet PA recommendations[71]. In NAFLD patients, compliance may be even lower because fatigue has been demonstrated to be markedly higher in NAFLD patients compared to controls, and is associated with inactivity and excessive daytime sleepiness[10]. Therefore, an alternative or a complement form of exercise that may be easier to perform or to adhere to, such as RT [raysistance training], may be helpful in the treatment of NAFLD patients."

 

[Amazoniac]

High Fructose Feeding Induces Copper Deficiency in Sprague-Dawley rats: A Novel Mechanism for Obesity Related Fatty Liver

"Recently, decreased hepatic copper concentrations were observed in NAFLD patients and were correlated with alterations in iron metabolism [9]. The mechanism underlying copper deficiency-associated hyperlipidemia is not fully understood. One potential mechanism is iron overload, which can occur secondary to copper deficiency [10]. Importantly, the source of dietary carbohydrate can play a critical role in the development of complications of copper deficiency. Extensive literature from the early 1980s showed that dietary fructose markedly enhanced the metabolic complications of copper deficiency in rodents [6, 11–13]. Research by Fields and co-workers showed that fructose-fed copper deficient male rats had lower hematocrits, but increased liver weight, cholesterol and triglycerides; whereas those fed starch had the least complications [6, 11, 12]. The mechanisms for these interactions are not well defined. Previous studies suggested that fructose-exacerbated copper deficiency might be due, in part, to impaired gut absorption of copper [14, 15].

Recent research showed that a significant proportion of NAFLD patients were copper deficient [9]. Heavy fructose consumption is a well-recognized risk factor for NAFLD. Given that excess dietary fructose exacerbates copper deficiency and copper deficiency induces fatty liver and hyperlipidemia, we hypothesized that the hyperlipidemia and fatty liver seen in high fructose-induced NAFLD is due, in part, to copper deficiency, and marginal dietary copper intake may be an initial component in the “two-hit” model of nonalcoholic steatohepatitis [35]."

"As expected, fructose feeding led to a significant increase in hepatic triglyceride content in both adequate copper and marginal copper deficient rats. However, marginal copper deficiency and fructose feeding addictively increased hepatic triglyceride accumulation."

"Because of its metabolic pathways, fructose rapidly induces hepatic de novo lipogenesis. Moreover, increased intestinal permeability associated with high fructose feeding may lead to endotoxemia and increase the secretion of inflammatory cytokines, which, in turn, can lead to insulin resistance and fatty liver [22]. However, even with increased de novo lipogenesis, steatosis should only occur when lipid export or fatty acid β-oxidation is decreased, suggesting that other mechanisms may be involved in the deleterious effects of fructose on the liver."

"Our present study demonstrated that fructose consumption further impaired marginal copper status and precipitated copper deficiency, possibly by inhibiting Ctr-1 mediated copper absorption through the intestinal epithelium. Moreover, marginal copper deficiency and fructose appeared to act together to exacerbate liver injury and accelerate hepatic fat accumulation. Copper deficiency-associated mitochondrial dysfunction and antioxidant defense system suppression primed the liver to fructose toxicity, possibly through the hepatic iron overload secondary to copper deficiency. Decreased mitochondrial fatty acid β-oxidation caused by copper deficiency represents a likely important mechanism underlying fructose induced fatty liver in this study. In addition, copper deficiency may induce insulin resistance and increase de novo lipogenesis which both contribute to hepatic lipid accumulation through multiple pathways."

"Marginal copper plus fructose caused a significant increase in both ALT and AST, with the AST being the most prominent (up to 5 fold), suggesting that fructose and copper deficiency act synergistically to cause liver injury."

"Our data showed that hepatic iron was significantly increased in marginal copper deficiency rats fed with fructose, and iron is a catalyst to convert hydrogen peroxide to hydroxyl radicals through Haber-Weiss and Fenton reactions. This may, in turn, impair mitochondria, leading to mitochondrial dysfunction and cell death. Thus, copper deficiency induced liver injury may be mediated, in part, through increased iron accumulation."

"We also showed that hepatic FAS [fatty acid synthase] expression was up-regulated by copper deficiency, suggesting enhanced de novo lipogenesis which may further contribute to lipid accumulation. However, [as mentioned a few posts back, ]de novo lipogenesis only accounts for a small part of hepatic free fatty acids [29], therefore, it appears that impaired mitochondrial fatty acid β-oxidation likely plays an important role in fructose induced NAFLD."

"Our data clearly showed that hepatic and whole body iron levels moved in the opposite direction of copper levels, suggesting that iron overload secondary to copper deficiency is another likely mechanism by which copper deficiency induces fatty liver."

"In conclusion, our data demonstrated that fructose feeding further impaired copper status and led to iron overload in marginal copper deficient rats. Dietary marginal copper deficiency and fructose feeding work together to exacerbate liver injury and accelerate hepatic fat accumulation, possibly mediated through increased iron accumulation. Therefore, high fructose-induced NAFLD may be due, in part, to copper deficiency. Decreased mitochondrial fatty acid β-oxidation caused by copper deficiency plays an important role in fructose induced fatty liver."​

--
Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

"Systemic iron homeostasis is equilibrated by the peptide hepcidin (hepatic bactericidal protein) mainly derived from hepatocytes and regulated by iron status, hypoxia, anemia and inflammation[10-12]. Hepcidin impacts on iron trafficking by attaching to FPN [ferroportin] which leads to the degradation of FPN and thereby to down-regulation of iron export inducing a decline in serum iron concentrations[13]. Quantitatively hepatocytes are the most important source for hepcidin, however, expression has also been reported in adipose tissue, pancreatic islets, macrophages, and even cardiac myocytes. Hence, iron homeostasis via FPN mediated iron export may be regulated in an autocrine fashion in these cells[14-16].

Perturbations of iron homeostasis are frequently observed in patients suffering from non-alcoholic fatty liver disease (NAFLD)[17,18]. As the prevalence of obesity rises, NAFLD with or without associated metabolic syndrome (MetS), has become the most frequent cause of hyperferritinemia. The first report of non-hemochromatotic iron overload linked to metabolic characteristics such as insulin resistance and overweight in a French study subsequently stimulated extensive research on the potential mechanisms underlying iron accumulation in NAFLD[19]. The dysmetabolic iron overload syndrome (DIOS) commonly refers to the characteristic association of fatty liver with moderate histological iron deposition (hemosiderosis) and increased serum ferritin[17,20]."

"The mild degree of body iron excess compared to markedly raised serum ferritin concentrations suggests that iron overload in NAFLD subjects results from a combination of alimentary and inflammatory driven iron loading and retention[20,29,30]. This is in line with the current evidence that NAFLD is both a metabolic and an inflammatory disease[31]."

"glucose metabolism and iron homeostasis appear to be functionally interconnected, due to the fact that gluconeogenetic signals regulate iron homeostasis via hepcidin[34] while iron loading or deficiency directly affect circulating glucose concentrations in mammals most likely via its effects on citric acid cycle enzyme activities[35,36], thereby also affecting lipid profiles[37]."

"It has been well recognized that iron overload leads to diabetes in patients with hemochromatosis where IR increases and insulin secretion decreases with the rise of body iron stores[25,80-82]. Hepatic insulin sensitivity and insulin secretion are re-established in the majority once iron is removed[83,84]. However, the prediabetic stage in hemochromatotic mice and humans displays impaired β-cell function along with increased insulin sensitivity, whereas dietary iron overload similar to the prediabetic state in humans are characterized by peripheral IR[85]. Hence, lessons drawn from hemochromatosis models are likely not fully applicable to the role of iron in human IR and NAFLD."

"Iron is well-recognized as a catalyst for the production of reactive oxygen intermediates via the Fenton reaction, and it is generally held that an increase of oxidative stress is a central mechanism for IR although direct proof for this hypothesis has not been obtained so far. Oxidative stress is a central pathogenic factor in NAFLD, T2DM and obesity[86-88] and markers of oxidative stress were increased in NAFLD with iron loading as compared to NAFLD without iron excess[68,89,90]. Generation of ROS may induce lipid peroxidation and cellular damage which may contribute to the progression of NAFLD."

"Liver macrophages named Kupffer cells, which are an important site of iron storage in NAFLD, are tightly involved in the initiation of the hepatic inflammatory cascade in response to the uptake of oxidized lipoproteins[104] or oxidized phosphatidylcholines[105]."

"Hepcidin expression davefostertheauthor correlated directly with liver iron indicating an intact physiological response of hepcidin biosynthesis to iron in the liver[28,114]."

"Recently, a detailed examination revealed an interaction of a high-fructose diet (which is also a culprit in the rise of obesity-related conditions) with low copper intake in triggering liver steatosis and damage as well as iron overload. Fructose acts as an inhibitor of duodenal copper absorption thereby leading to impaired oxidant defense and augmented lipid peroxidation[above]."

"copper is necessary for ceruloplasmin function to export iron from the liver or the RES and also for FPN expression[138]. Expression of a membrane-bound form of ceruloplasmin is mandatory for stable FPN expression[139,140]. Accordingly, a lack of ceruloplasmin as found in the heritable disease aceruloplasminemia leads to tissue iron accumulation and damage most notably in the brain[141].

Low liver and serum copper concentrations were reported in iron overloaded NAFLD and were linked to decreased ferroxidase activity of ceruloplasmin[122]. The expression of FPN was found to be decreased in livers of rats on a copper deficient diet. These observations provide evidence that in addition to decreased FPN expression due to low-grade systemic inflammation, low copper bioavailability contributes to iron retention in NAFLD."

"Elimination of iron may confer a beneficial effect on IR-associated conditions. Removal of iron using phlebotomies is usually well tolerated, with the caution that DIOS patients frequently show a fast decline in TfS [transuchin saturation] [142]. These clinical observations are expected due to the underlying molecular mechanisms of impaired iron export." chelationnation.com

"Blood donations were linked to insulin sensitivity even in healthy subjects[46]. Studies on iron depletion in NAFLD in humans have demonstrated benefits regarding systemic or hepatic insulin resistance and pancreatic insulin sensitivity[142,147,148]. A randomized trial demonstrated improved HbA1c, insulin sensitivity and secretion subjects who received phlebotomy treatment[149]. The effects of iron depletion were additive to successful lifestyle modifications[150]. Similar observations were reported the effect of iron depletion on other cardiovascular risk factors[151] and iron removal may prevent development and progression of malignancies[152]."​

--
Secondary causes of nonalcoholic fatty liver disease

"Corticosteroids cause steatosis by inhibiting mitochondrial beta-oxidation and lipid beta-peroxidation enzymes, leading to the accumulation of lipids within hepatocytes. Corticosteroids also induce de novo fatty acid synthesis by activating lipogenic enzymes such as fatty acid synthase, acetyl-CoA carboxylase, and 11 beta-HSD1 in the liver [Jia et al. 2009]. Corticosteroids also contribute to the development of insulin resistance and hyperinsulinemia leading to lipogenesis in the liver."

"[In Wilson's disease, copper] cannot be excreted in the bile and accumulates in a variety of tissues including hepatocytes. In the liver, the excess copper impairs mitochondrial function and fatty acid beta-oxidation, leading to steatosis. Liver histology is variable and ranges from histologic features indistinguishable from NASH due to metabolic syndrome (Figure 5) to chronic hepatitis due to submassive or massive hepatic necrosis. A copper stain may be helpful, although a negative stain does not exclude the disease and copper quantification may be required for diagnosis. Chelating regimens such as penicillamine, trientine, and zinc are the standard therapy [Farinati et al. 2003]."
"Biounavailability"​

--
A role for low hepatic copper concentrations in nonalcoholic Fatty liver disease. - PubMed - NCBI

 

[Amazoniac]

The effect of vitamin E on lipid peroxidation in the copper-deficient rat - ScienceDirect

--
Caffeine Is Protective Against Liver Disease

 

[Regina]

High Fructose Feeding Induces Copper Deficiency in Sprague-Dawley rats: A Novel Mechanism for Obesity Related Fatty Liver

"Recently, decreased hepatic copper concentrations were observed in NAFLD patients and were correlated with alterations in iron metabolism [9]. The mechanism underlying copper deficiency-associated hyperlipidemia is not fully understood. One potential mechanism is iron overload, which can occur secondary to copper deficiency [10]. Importantly, the source of dietary carbohydrate can play a critical role in the development of complications of copper deficiency. Extensive literature from the early 1980s showed that dietary fructose markedly enhanced the metabolic complications of copper deficiency in rodents [6, 11–13]. Research by Fields and co-workers showed that fructose-fed copper deficient male rats had lower hematocrits, but increased liver weight, cholesterol and triglycerides; whereas those fed starch had the least complications [6, 11, 12]. The mechanisms for these interactions are not well defined. Previous studies suggested that fructose-exacerbated copper deficiency might be due, in part, to impaired gut absorption of copper [14, 15].

Recent research showed that a significant proportion of NAFLD patients were copper deficient [9]. Heavy fructose consumption is a well-recognized risk factor for NAFLD. Given that excess dietary fructose exacerbates copper deficiency and copper deficiency induces fatty liver and hyperlipidemia, we hypothesized that the hyperlipidemia and fatty liver seen in high fructose-induced NAFLD is due, in part, to copper deficiency, and marginal dietary copper intake may be an initial component in the “two-hit” model of nonalcoholic steatohepatitis [35]."

"As expected, fructose feeding led to a significant increase in hepatic triglyceride content in both adequate copper and marginal copper deficient rats. However, marginal copper deficiency and fructose feeding addictively increased hepatic triglyceride accumulation."

"Because of its metabolic pathways, fructose rapidly induces hepatic de novo lipogenesis. Moreover, increased intestinal permeability associated with high fructose feeding may lead to endotoxemia and increase the secretion of inflammatory cytokines, which, in turn, can lead to insulin resistance and fatty liver [22]. However, even with increased de novo lipogenesis, steatosis should only occur when lipid export or fatty acid β-oxidation is decreased, suggesting that other mechanisms may be involved in the deleterious effects of fructose on the liver."

"Our present study demonstrated that fructose consumption further impaired marginal copper status and precipitated copper deficiency, possibly by inhibiting Ctr-1 mediated copper absorption through the intestinal epithelium. Moreover, marginal copper deficiency and fructose appeared to act together to exacerbate liver injury and accelerate hepatic fat accumulation. Copper deficiency-associated mitochondrial dysfunction and antioxidant defense system suppression primed the liver to fructose toxicity, possibly through the hepatic iron overload secondary to copper deficiency. Decreased mitochondrial fatty acid β-oxidation caused by copper deficiency represents a likely important mechanism underlying fructose induced fatty liver in this study. In addition, copper deficiency may induce insulin resistance and increase de novo lipogenesis which both contribute to hepatic lipid accumulation through multiple pathways."

"Marginal copper plus fructose caused a significant increase in both ALT and AST, with the AST being the most prominent (up to 5 fold), suggesting that fructose and copper deficiency act synergistically to cause liver injury."

"Our data showed that hepatic iron was significantly increased in marginal copper deficiency rats fed with fructose, and iron is a catalyst to convert hydrogen peroxide to hydroxyl radicals through Haber-Weiss and Fenton reactions. This may, in turn, impair mitochondria, leading to mitochondrial dysfunction and cell death. Thus, copper deficiency induced liver injury may be mediated, in part, through increased iron accumulation."

"We also showed that hepatic FAS [fatty acid synthase] expression was up-regulated by copper deficiency, suggesting enhanced de novo lipogenesis which may further contribute to lipid accumulation. However, [as mentioned a few posts back, ]de novo lipogenesis only accounts for a small part of hepatic free fatty acids [29], therefore, it appears that impaired mitochondrial fatty acid β-oxidation likely plays an important role in fructose induced NAFLD."

"Our data clearly showed that hepatic and whole body iron levels moved in the opposite direction of copper levels, suggesting that iron overload secondary to copper deficiency is another likely mechanism by which copper deficiency induces fatty liver."

"In conclusion, our data demonstrated that fructose feeding further impaired copper status and led to iron overload in marginal copper deficient rats. Dietary marginal copper deficiency and fructose feeding work together to exacerbate liver injury and accelerate hepatic fat accumulation, possibly mediated through increased iron accumulation. Therefore, high fructose-induced NAFLD may be due, in part, to copper deficiency. Decreased mitochondrial fatty acid β-oxidation caused by copper deficiency plays an important role in fructose induced fatty liver."​

--
Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

"Systemic iron homeostasis is equilibrated by the peptide hepcidin (hepatic bactericidal protein) mainly derived from hepatocytes and regulated by iron status, hypoxia, anemia and inflammation[10-12]. Hepcidin impacts on iron trafficking by attaching to FPN [ferroportin] which leads to the degradation of FPN and thereby to down-regulation of iron export inducing a decline in serum iron concentrations[13]. Quantitatively hepatocytes are the most important source for hepcidin, however, expression has also been reported in adipose tissue, pancreatic islets, macrophages, and even cardiac myocytes. Hence, iron homeostasis via FPN mediated iron export may be regulated in an autocrine fashion in these cells[14-16].

Perturbations of iron homeostasis are frequently observed in patients suffering from non-alcoholic fatty liver disease (NAFLD)[17,18]. As the prevalence of obesity rises, NAFLD with or without associated metabolic syndrome (MetS), has become the most frequent cause of hyperferritinemia. The first report of non-hemochromatotic iron overload linked to metabolic characteristics such as insulin resistance and overweight in a French study subsequently stimulated extensive research on the potential mechanisms underlying iron accumulation in NAFLD[19]. The dysmetabolic iron overload syndrome (DIOS) commonly refers to the characteristic association of fatty liver with moderate histological iron deposition (hemosiderosis) and increased serum ferritin[17,20]."

"The mild degree of body iron excess compared to markedly raised serum ferritin concentrations suggests that iron overload in NAFLD subjects results from a combination of alimentary and inflammatory driven iron loading and retention[20,29,30]. This is in line with the current evidence that NAFLD is both a metabolic and an inflammatory disease[31]."

"glucose metabolism and iron homeostasis appear to be functionally interconnected, due to the fact that gluconeogenetic signals regulate iron homeostasis via hepcidin[34] while iron loading or deficiency directly affect circulating glucose concentrations in mammals most likely via its effects on citric acid cycle enzyme activities[35,36], thereby also affecting lipid profiles[37]."

"It has been well recognized that iron overload leads to diabetes in patients with hemochromatosis where IR increases and insulin secretion decreases with the rise of body iron stores[25,80-82]. Hepatic insulin sensitivity and insulin secretion are re-established in the majority once iron is removed[83,84]. However, the prediabetic stage in hemochromatotic mice and humans displays impaired β-cell function along with increased insulin sensitivity, whereas dietary iron overload similar to the prediabetic state in humans are characterized by peripheral IR[85]. Hence, lessons drawn from hemochromatosis models are likely not fully applicable to the role of iron in human IR and NAFLD."

"Iron is well-recognized as a catalyst for the production of reactive oxygen intermediates via the Fenton reaction, and it is generally held that an increase of oxidative stress is a central mechanism for IR although direct proof for this hypothesis has not been obtained so far. Oxidative stress is a central pathogenic factor in NAFLD, T2DM and obesity[86-88] and markers of oxidative stress were increased in NAFLD with iron loading as compared to NAFLD without iron excess[68,89,90]. Generation of ROS may induce lipid peroxidation and cellular damage which may contribute to the progression of NAFLD."

"Liver macrophages named Kupffer cells, which are an important site of iron storage in NAFLD, are tightly involved in the initiation of the hepatic inflammatory cascade in response to the uptake of oxidized lipoproteins[104] or oxidized phosphatidylcholines[105]."

"Hepcidin expression davefostertheauthor correlated directly with liver iron indicating an intact physiological response of hepcidin biosynthesis to iron in the liver[28,114]."

"Recently, a detailed examination revealed an interaction of a high-fructose diet (which is also a culprit in the rise of obesity-related conditions) with low copper intake in triggering liver steatosis and damage as well as iron overload. Fructose acts as an inhibitor of duodenal copper absorption thereby leading to impaired oxidant defense and augmented lipid peroxidation[above]."

"copper is necessary for ceruloplasmin function to export iron from the liver or the RES and also for FPN expression[138]. Expression of a membrane-bound form of ceruloplasmin is mandatory for stable FPN expression[139,140]. Accordingly, a lack of ceruloplasmin as found in the heritable disease aceruloplasminemia leads to tissue iron accumulation and damage most notably in the brain[141].

Low liver and serum copper concentrations were reported in iron overloaded NAFLD and were linked to decreased ferroxidase activity of ceruloplasmin[122]. The expression of FPN was found to be decreased in livers of rats on a copper deficient diet. These observations provide evidence that in addition to decreased FPN expression due to low-grade systemic inflammation, low copper bioavailability contributes to iron retention in NAFLD."

"Elimination of iron may confer a beneficial effect on IR-associated conditions. Removal of iron using phlebotomies is usually well tolerated, with the caution that DIOS patients frequently show a fast decline in TfS [transuchin saturation] [142]. These clinical observations are expected due to the underlying molecular mechanisms of impaired iron export." chelationnation.com

"Blood donations were linked to insulin sensitivity even in healthy subjects[46]. Studies on iron depletion in NAFLD in humans have demonstrated benefits regarding systemic or hepatic insulin resistance and pancreatic insulin sensitivity[142,147,148]. A randomized trial demonstrated improved HbA1c, insulin sensitivity and secretion subjects who received phlebotomy treatment[149]. The effects of iron depletion were additive to successful lifestyle modifications[150]. Similar observations were reported the effect of iron depletion on other cardiovascular risk factors[151] and iron removal may prevent development and progression of malignancies[152]."​

--
Secondary causes of nonalcoholic fatty liver disease

"Corticosteroids cause steatosis by inhibiting mitochondrial beta-oxidation and lipid beta-peroxidation enzymes, leading to the accumulation of lipids within hepatocytes. Corticosteroids also induce de novo fatty acid synthesis by activating lipogenic enzymes such as fatty acid synthase, acetyl-CoA carboxylase, and 11 beta-HSD1 in the liver [Jia et al. 2009]. Corticosteroids also contribute to the development of insulin resistance and hyperinsulinemia leading to lipogenesis in the liver."

"[In Wilson's disease, copper] cannot be excreted in the bile and accumulates in a variety of tissues including hepatocytes. In the liver, the excess copper impairs mitochondrial function and fatty acid beta-oxidation, leading to steatosis. Liver histology is variable and ranges from histologic features indistinguishable from NASH due to metabolic syndrome (Figure 5) to chronic hepatitis due to submassive or massive hepatic necrosis. A copper stain may be helpful, although a negative stain does not exclude the disease and copper quantification may be required for diagnosis. Chelating regimens such as penicillamine, trientine, and zinc are the standard therapy [Farinati et al. 2003]."
"Biounavailability"​

--
A role for low hepatic copper concentrations in nonalcoholic Fatty liver disease. - PubMed - NCBI

Once again, a fantastic offering. Thank you.
I think haidut's going to be making a succinic acid product that might help our rat's livers.
It's a terrible pairing with coffee/milk, but lately my morning meal has a side of water with 1/2 tsp of malic acid.

 

[Wagner83]

Isn't a lot of what you posted along the lines of what gboluev said?

 

[Amazoniac]

Once again, a fantastic offering. Thank you.
I think haidut's going to be making a succinic acid product that might help our rat's livers.
It's a terrible pairing with coffee/milk, but lately my morning meal has a side of water with 1/2 tsp of malic acid.

Vit C affects internal iron but also copper and zinc. So it's one more thing to consider.
Have you tried magnesium malate? Since it's just a temporary thing, a bit of lead from magnesium won't be too much of a problem, especially in the presence of calcium. It's more neutral in terms of taste and (if I'm not wrong) will provide you the same effect when digested.

 

[Amazoniac]

Isn't a lot of what you posted along the lines of what gboluev said?

I don't know what exactly you have in mind, but if so, things are converging here..

 

[Wagner83]

I don't know what exactly you have in mind, but if so, things are converging here..

Not sure either . Sounds like not retaining much copper in the liver could be worthy in gbol's world, and the studies may be contradicting gbol:
Bicarbonate Vs. PaCO2 Blood Tests
He repeatedly said slow oxidizers should avoid liver and copper since they retain copper in their liver like crazy.

I had posted a study on how a sucrose/high fructose diet led to elevated adrenaline and noradrenaline concentrations.
This quote goes well with it:

"Same as any one with certain cancers can get rid of it with running. I recommended this to many people with cancers and many got rid of cancers. they increased their sympathetic nervous system and hyperventilated , this caused you to dump copper. SINCE COPPER IS RETAINed when you are hypoventilating , your ceruloplasmin is low.

And ceruloplasmin goes up with a SHOT OF ADRENALINE. since if adrenaline is high , body will start dumping copper,since body will want to use serotonin

Read Ecks work. He explains it well.

And Peat says people are losing copper LOL. is that why when you eat livers it is full of copper and iron? IT IS FULL OF COPPER , topped up with COPPER. Since body is retaining it. And most animals have the same issue. Especially home grown animals with little stress."

 

[Amazoniac]

Not sure either . Sounds like not retaining much copper in the liver could be worthy in gbol's world, and the studies may be contradicting gbol:
Bicarbonate Vs. PaCO2 Blood Tests
He repeatedly said slow oxidizers should avoid liver and copper since they retain copper in their liver like crazy.

I had posted a study on how a sucrose/high fructose diet led to elevated adrenaline and noradrenaline concentrations.
This quote goes well with it:

"Same as any one with certain cancers can get rid of it with running. I recommended this to many people with cancers and many got rid of cancers. they increased their sympathetic nervous system and hyperventilated , this caused you to dump copper. SINCE COPPER IS RETAINed when you are hypoventilating , your ceruloplasmin is low.

And ceruloplasmin goes up with a SHOT OF ADRENALINE. since if adrenaline is high , body will start dumping copper,since body will want to use serotonin

Read Ecks work. He explains it well.

And Peat says people are losing copper LOL. is that why when you eat livers it is full of copper and iron? IT IS FULL OF COPPER , topped up with COPPER. Since body is retaining it. And most animals have the same issue. Especially home grown animals with little stress."

Actually the prevalent signal in slow metabolisms is to decrease everything, because you have difficulty balancing all nutrients, so everything tends to be excessive or accumulate. Personally, I don't think that the solution is to increase copper or caffeine, but to eat sugars to appetite.

I believe that this quote summarizes the best approach when it comes to solving these issues because the majority of inflammation initiates in the gut:
[For healing or strengthening the lining of... | Ray Peat Forum
I would only add potassium and vit C; and some calcium and sodium but not too much.
When people are given antibiotics the situation improves right away (even when they aren't much absorbable).

As a example, I mentioned this doctor a lot of times and I like her because her main observations were made during a period in which she was still naive and not much influenced by nutrition. Regardless of her explanations, she notice that her patients needed plenty of vits B and D. As D normalized, they started to need less and less of the B-vits. It should be counterproductive to have an abundance of B-vits during hibernation, you only need some for basic functions, but as hibernation ceases, it's beneficial to have plenty of them again. She hypothesizes that it's based on germ manipulation in the intestines. But the point is: it's getting easier and easier to do everything without even stepping outside of your house; work, buy food, exercise, order prostitutes, etc. So a deficiency affects everything. I believe this indeed shouldn't be overlooked:

Vitamin D and calcium, both have a direct suppressive effect on fat formation. The fatty liver for example, in animal studies it is corrected by both, vitamin D and calcium.

 

[Amazoniac]

I'm not sure if I commented this elsewhere, but one of the craziest persons that I ever met was a woman who owned a small company. Every time I met her I was puzzled by how she didn't collapse. She was freaking out the whole time, skipping meals in a bizarre fashion, downing any food in a rush, screaming with anger at her employees, disrespectful to her secretary, etc. The only unusual thing about her was that she always had a marked tan. I have no doubt that vit D was one of the main factors holding her in place.

 

[Regina]

Vit C affects internal iron but also copper and zinc. So it's one more thing to consider.
Have you tried magnesium malate? Since it's just a temporary thing, a bit of lead from magnesium won't be too much of a problem, especially in the presence of calcium. It's more neutral in terms of taste and (if I'm not wrong) will provide you the same effect when digested.

Thx. I have added vit C. I either take Pure Enc mag glysinate or "Mineral 650" or "Muscle Cramps".
Things have improved. I have no idea what my 5 month brush with zombiehood was all about, but it seems to have passed.
I'm back to training just fine again. And also, (tmi) my periods have returned ; well, i.e., if two in a row make a trend.

 

[Amazoniac]

(tmi) my periods have returned

There were "mucoid plaques" being posted here, they primed me for LiveLeak.

 

[Regina]

Actually the prevalent signal in slow metabolisms is to decrease everything, because you have difficulty balancing all nutrients, so everything tends to be excessive or accumulate. Personally, I don't think that the solution is to increase copper or caffeine, but to eat sugars to appetite.

I believe that this quote summarizes the best approach when it comes to solving these issues because the majority of inflammation initiates in the gut:
[For healing or strengthening the lining of... | Ray Peat Forum
I would only add potassium and vit C; and some calcium and sodium but not too much.
When people are given antibiotics the situation improves right away (even when they aren't much absorbable).

As a example, I mentioned this doctor a lot of times and I like her because her main observations were made during a period in which she was still naive and not much influenced by nutrition. Regardless of her explanations, she notice that her patients needed plenty of vits B and D. As D normalized, they started to need less and less of the B-vits. It should be counterproductive to have an abundance of B-vits during hibernation, you only need some for basic functions, but as hibernation ceases, it's beneficial to have plenty of them again. She hypothesizes that it's based on germ manipulation in the intestines. But the point is: it's getting easier and easier to do everything without even stepping outside of your house; work, buy food, exercise, order prostitutes, etc. So a deficiency affects everything. I believe this indeed shouldn't be overlooked:

hookers and cocaine