The Hepatitis C virus replicates and infects cells by hijacking at least two cellular mechanisms, one of which is specific to liver cells; the RNA replication apparatus, which is essential in all cells (and thus is not a realistic target for nutritional therapy), and the mechanism which converts excess carbohydrate to triglycerides (fatty acids) and sends them to the blood stream to be stored in fat cells for later use.
The latter mechanism is largely optional, and is sent into overdrive by the high carbohydrate of the current, fashionable, “healthy” diet.
The human body has evolved to function on minimal or no carbohydrates, because we evolved under conditions, before the invention of agriculture, where game animals, birds, and fish were plentiful and most available plant sources of nutrition were relatively low in carbohydrates and rich in polyphenols and fibre (bitter or tart, and stringy) compared to those we eat today.
DGAT1 is a liver enzyme essential for HCV replication the production of which is triggered by insulin, which is the hormone the body produces in reaction to glucose, the digestion product of most carbohydrate foods, and more specifically in the liver by fructose, derived from sugar (sucrose) and fruit juice. Blocking DGAT1 is considered to be a realistic target of drug therapies for HCV. However, it is doubtful that any drug it is possible to invent could lower the level of DGAT1 as completely as a diet with no use for it; that is to say, a diet with minimal fructose and no more carbohydrate than can be burned for energy immediately (a very small amount unless you are an athlete in the middle of performance), or could lower DGAT1 without other unwanted effects. Once replicated, HCV escapes from infected hepatocytes via the membrane sites that release VLDL-"cholesterol" into the bloodstream. VLDL carries the triglycerides which have been formed to store the energy from excess carbohydrate (once these are dumped into fat storage VLDL becomes the notorious LDL. The more triglycerides packed into the original VLDL, the more harmful the type of LDL). HCV enters and infects new cells in tandem with LDL, using the LDL receptor. If you use oil or spreads high in "heart healthy" PUFA, including fish oil, the cells express more LDL receptors to pull more LDL from the blood. People with Hep C actually do better if their LDL levels are higher. PUFAs create an increased need for cholesterol; the cell membranes become sloppier and need more cholesterol reinforcement. Liver production of cholesterol, and total body cholesterol content, actually increases on a diet high in PUFA, while the blood level (serum cholesterol) is lowered.
The virus seeks to monopolize cholesterol production in order to reduce serum cholesterol and LDL; low cholesterol and LDL has the effect of increasing LDL receptors; the increased availability of receptors in a low-cholesterol environment maximizes HCV's access to naive cells via its own association with LDL.
Consuming cholesterol-rich foods in the diet also has the effect of reducing LDL receptors, especially in the context of a low-carbohydrate diet, and also reduces hepatic activity of HMG-Co reductase, an enzyme that may be essential in the early stages of HCV infection, and which remains in use by genotype 3.
Thus restricting fructose, total carbohydrate, and PUFA* and eating a cholesterol-rich diet produces three effects on HCV; 1) replication is slowed because less DGAT1 (and less HMG-CoA reductase) is expressed, 2) serum HCV level is lowered because less of the HCV is being secreted from infected hepatocytes. 3) less HCV is being taken up into uninfected hepatocytes. A further benefit is the improved immune function seen on low carb diets, as high insulin and glucose levels compromise immunity. The decreased expression of HCV core proteins also improves immunity, liver function and antioxidant status. Fibrosis is also heavily driven by insulin and all inflammatory processes are slowed or stopped by the serious reduction of carbohydrates. Eating a low carb diet means eating more fats and protein, and these have positive benefits for liver health; protein is a mixture of amino acids, almost all of which have been shown to have anti-inflammatory or antioxidant effects at the concentrations in a high-protein diet, and none of which are harmful (there is no evidence that high protein intake harms the kidneys; the sole experimental finding that began this myth resulted from feeding a diet of meat and soy protein to caged rabbits, an animal which naturally eats very little protein in its diet. If you feed a carnivorous or omnivorous animal a higher-protein diet its kidneys will, if anything, function better than they did before). As for fats, we have been lied to for years ("A lie can travel halfway round the world while the truth is still putting on its shoes" - Mark Twain). Saturated fats do not cause disease, and polyunsaturated fats are not necessarily healthy. A diet including beef tallow, the most saturated of animal fats, protects the liver of rats force-fed alcohol, and such diets are at the heart of the so-called French paradox; populations that drink heavily and eat most saturated fat have the lowest levels of heart disease and cirrhosis. We do not need to invoke resveratrol to explain this result.
(* PUFAs arachadonic acid, EPA, and DHA have antiviral effects on HCV replication, but are profibrotic at higher intakes.)
Dietary Saturated Fatty Acids Reverse Inflammatory and Fibrotic Changes in Rat Liver Despite Continued Ethanol Administration Amin A. Nanji1, Kalle Jokelainen2, George L. Tipoe3, Amir Rahemtulla4 and Andrew J. Dannenberg5 ananji@pathology.hku.hk http://jpet.aspetjournals.org/content/299/2/638.long
Abstract
We investigated the potential of dietary saturated fatty acids to reverse alcoholic liver injury despite continued administration of alcohol. Five groups (six rats/group) of male Wistar rats were studied. Rats in groups 1 and 2 were fed a fish oil-ethanol diet for 8 and 6 weeks, respectively. Rats in groups 3 and 4 were fed fish oil and ethanol for 6 weeks before being switched to isocaloric diets containing ethanol with palm oil (group 3) or medium-chain triglycerides (MCTs, group 4) for 2 weeks. Rats in group 5 were fed fish oil and dextrose for 8 weeks. Liver samples were analyzed for histopathology, lipid peroxidation, nuclear factor-κB (NF-κB) activation, and mRNAs for cyclooxygenase-2 (Cox-2) and tumor necrosis factor-α (TNF-α). Endotoxin in plasma was determined. The most severe inflammation and fibrosis were detected in groups 1 and 2, as were the highest levels of endotoxin, lipid peroxidation, activation of NF-κB, and mRNAs for Cox-2 and TNF-α. After the rats were switched to palm oil or MCT, there was marked histological improvement with decreased levels of endotoxin and lipid peroxidation, absence of NF-κB activation, and reduced expression of TNF-α and Cox-2. A diet enriched in saturated fatty acids effectively reverses alcohol-induced necrosis, inflammation, and fibrosis despite continued alcohol consumption. The therapeutic effects of saturated fatty acids may be explained, at least in part, by reduced endotoxemia and lipid peroxidation, which in turn result in decreased activation of NF-κB and reduced levels of TNF-α and Cox-2. Long-term treatment of alcoholic liver disease continues to incorporate vitamins, nutrients, and trace elements (Fulton and McCullough, 1998; McCullough et al., 1998). In fact, the role of specific pharmacological agents remains unproven. Clearly, the development of more effective nutritional or pharmacological therapy will depend on further elucidating the mechanisms that contribute to liver injury. Several lines of investigation indicate that dietary fat can modulate the severity of alcoholic liver injury (Mezey, 1998). In experimental animals, for example, diets enriched with saturated fatty acids protect against alcohol-induced liver injury, whereas diets containing polyunsaturated fatty acids promote liver injury (Nanji and French, 1989; Nanji et al., 1989, 1994a). Saturated fatty acids have also been reported to reverse established alcoholic liver injury (Nanji et al., 1995, 1996, 1997b). Importantly, in previous studies, use of alcohol was discontinued at the time that dietary treatment was initiated. This model represented the alcoholic patient who stopped drinking at the time of hospitalization (French, 1995). Discontinuation of alcohol remains pivotal in the treatment of alcoholic liver disease. Although this goal can frequently be achieved in the short-term, the majority of patients resume alcohol consumption, often with sudden deterioration in liver disease (Pares et al., 1986). Hence, it is important to develop therapeutic strategies that simulate the clinical condition in which alcohol use is continued despite the presence of alcoholic liver disease. Previously, we used the intragastric feeding rat model to study the pathogenesis of alcoholic liver disease (Nanji et al., 1999). In addition to being useful for elucidating mechanisms of injury, this model has been used to evaluate various strategies to prevent or reverse alcoholic liver disease (Nanji et al., 1995, 1997b). The results of previous studies suggest that elevated levels of endotoxin and lipid peroxides in alcohol-fed animals activate nuclear factor-κB (NF-κB), leading to enhanced expression of tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (Cox-2), and proinflammatory cytokines (Nanji et al., 1997a, 1999). In the current study, we investigated whether treatment with dietary saturated fatty acids could reverse established alcoholic liver injury despite continued administration of ethanol. We show that diets enriched in saturated fatty acids improved both histological liver injury and biochemical parameters that have been etiologically linked to liver injury.
(The ferretin levels in the livers of the saturated-fat rats were less than half those of the polyunsaturated fat-rats).
Beef Fat Prevents Alcoholic Liver Disease in the Rat Amin A. Nanji MD, FRCP(C), Charles L.
The amount and type of dietary fat is thought to be important in the pathogenesis of alcoholic liver disease (ALD). We investigated the role of different dietary fats in our rat model for ALD. Liver pathology was evaluated in rats fed ethanol and lard or tallow or corn oil over a period of 2 to 6 months. All experimental animals were pair-fed the same diet as controls except that glucose was isocalorically replaced by ethanol. Rats fed tallow and ethanol developed none of the features of ALD, those fed lard and ethanol developed minimal to moderate disease, rats fed corn oil and ethanol developed the most severe pathology. The degree of histopathological abnormality correlated with the linoleic acid content of fat in the diet (tallow 0.7%, lard 2.5%, corn oil 56.6%). We postulate that linoleic acid facilitates development of ALD and provides an explanation for our previous epidemiological observations. Effect of Dietary Fat on Ito Cell Activation by Chronic Ethanol Intake: A Long-Term Serial Morphometric Study on Alcohol-Fed and Control Rats Hisao Takahashi, Kim Wong, Linda Jui, Amin A. Nanji, Charles S. Mendenhall, Samuel W. French (note: Ito Cells are Hepatic Stellate cells in their normal state. This study is saying that rats fed beef tallow had no loss of Ito cells – that is, no conversion to myofibroblasts – whereas rats fed corn oil went into fibrosis) We studied the effects of long-term ethanol ingestion and dietary fat on Ito cell activation morphometrically in rats. Sixteen pairs of Wistar male rats were divided into two groups, one fed tallow and the other fed corn oil as the source of dietary fat. Each group of rats were pair-fed a nutritional adequate liquid diet containing either corn oil (CF) or tallow (TF) as fat as well as protein and carbohydrate. Half of each group received ethanol, the rest were pair-fed isocaloric amounts of dextrose via an implanted gastric tube for up to 5 months. Morphometric analysis of the change in fat and rough endoplasmic reticulum (RER) of Ito cells was performed on electron micrographs obtained from monthly biopsies including baseline. Ito cell activation was assessed by a decrease in the ratio of fat/RER in Ito cells. The ratio of fat/RER in Ito cells of alcoholic rats fed the CF diet (CFA) gradually decreased. The ratio war found to be lower than in the pair-fed control rats (CFC) at 5 months of feeding. CFA 1.74 ± 0.57, vs. 7.46 ± 2.05, respectlvely, p < 0.05, mean ± se). Ito cell fat also significantly decreased at 5 months of feeding (p < 0.05). The fat/ RER ratio In CFA significantly decreased only subsequent to the development of fatty change, necrosis, and inflammation followed by fibrosis of the liver. In contrast, the TFA rats did not show a significant decrease in the fat/RER ratio in the Ito cells throughout the study, while TFC rats showed an increase in the fat/RER ratio. Minimal pathological changes were observed in the livers of CFC, TFA, and TFC rats. These results indicate that activation of Ito cells at a significant level occurred only late in the course of feeding alcohol after moderate to severe abnormalities in liver histology had developed, although activation may have begun at an earlier time of ethanol feeding. The results indicate that dietary fatty acid composition may be an important factor in the pathogenesis of ethanol-induced Ito cell activation.![]()
DGAT1 is a liver enzyme essential for HCV replication the production of which is triggered by insulin, which is the hormone the body produces in reaction to glucose, the digestion product of most carbohydrate foods, and more specifically in the liver by fructose, derived from sugar (sucrose) and fruit juice. Blocking DGAT1 is considered to be a realistic target of drug therapies for HCV. However, it is doubtful that any drug it is possible to invent could lower the level of DGAT1 as completely as a diet with no use for it; that is to say, a diet with minimal fructose and no more carbohydrate than can be burned for energy immediately (a very small amount unless you are an athlete in the middle of performance), or could lower DGAT1 without other unwanted effects. Once replicated, HCV escapes from infected hepatocytes via the membrane sites that release VLDL-"cholesterol" into the bloodstream. VLDL carries the triglycerides which have been formed to store the energy from excess carbohydrate (once these are dumped into fat storage VLDL becomes the notorious LDL. The more triglycerides packed into the original VLDL, the more harmful the type of LDL). HCV enters and infects new cells in tandem with LDL, using the LDL receptor. If you use oil or spreads high in "heart healthy" PUFA, including fish oil, the cells express more LDL receptors to pull more LDL from the blood. People with Hep C actually do better if their LDL levels are higher. PUFAs create an increased need for cholesterol; the cell membranes become sloppier and need more cholesterol reinforcement. Liver production of cholesterol, and total body cholesterol content, actually increases on a diet high in PUFA, while the blood level (serum cholesterol) is lowered.
The virus seeks to monopolize cholesterol production in order to reduce serum cholesterol and LDL; low cholesterol and LDL has the effect of increasing LDL receptors; the increased availability of receptors in a low-cholesterol environment maximizes HCV's access to naive cells via its own association with LDL.
Consuming cholesterol-rich foods in the diet also has the effect of reducing LDL receptors, especially in the context of a low-carbohydrate diet, and also reduces hepatic activity of HMG-Co reductase, an enzyme that may be essential in the early stages of HCV infection, and which remains in use by genotype 3.
Thus restricting fructose, total carbohydrate, and PUFA* and eating a cholesterol-rich diet produces three effects on HCV; 1) replication is slowed because less DGAT1 (and less HMG-CoA reductase) is expressed, 2) serum HCV level is lowered because less of the HCV is being secreted from infected hepatocytes. 3) less HCV is being taken up into uninfected hepatocytes. A further benefit is the improved immune function seen on low carb diets, as high insulin and glucose levels compromise immunity. The decreased expression of HCV core proteins also improves immunity, liver function and antioxidant status. Fibrosis is also heavily driven by insulin and all inflammatory processes are slowed or stopped by the serious reduction of carbohydrates. Eating a low carb diet means eating more fats and protein, and these have positive benefits for liver health; protein is a mixture of amino acids, almost all of which have been shown to have anti-inflammatory or antioxidant effects at the concentrations in a high-protein diet, and none of which are harmful (there is no evidence that high protein intake harms the kidneys; the sole experimental finding that began this myth resulted from feeding a diet of meat and soy protein to caged rabbits, an animal which naturally eats very little protein in its diet. If you feed a carnivorous or omnivorous animal a higher-protein diet its kidneys will, if anything, function better than they did before). As for fats, we have been lied to for years ("A lie can travel halfway round the world while the truth is still putting on its shoes" - Mark Twain). Saturated fats do not cause disease, and polyunsaturated fats are not necessarily healthy. A diet including beef tallow, the most saturated of animal fats, protects the liver of rats force-fed alcohol, and such diets are at the heart of the so-called French paradox; populations that drink heavily and eat most saturated fat have the lowest levels of heart disease and cirrhosis. We do not need to invoke resveratrol to explain this result.
(* PUFAs arachadonic acid, EPA, and DHA have antiviral effects on HCV replication, but are profibrotic at higher intakes.)
Dietary Saturated Fatty Acids Reverse Inflammatory and Fibrotic Changes in Rat Liver Despite Continued Ethanol Administration Amin A. Nanji1, Kalle Jokelainen2, George L. Tipoe3, Amir Rahemtulla4 and Andrew J. Dannenberg5 ananji@pathology.hku.hk http://jpet.aspetjournals.org/content/299/2/638.long
Abstract
We investigated the potential of dietary saturated fatty acids to reverse alcoholic liver injury despite continued administration of alcohol. Five groups (six rats/group) of male Wistar rats were studied. Rats in groups 1 and 2 were fed a fish oil-ethanol diet for 8 and 6 weeks, respectively. Rats in groups 3 and 4 were fed fish oil and ethanol for 6 weeks before being switched to isocaloric diets containing ethanol with palm oil (group 3) or medium-chain triglycerides (MCTs, group 4) for 2 weeks. Rats in group 5 were fed fish oil and dextrose for 8 weeks. Liver samples were analyzed for histopathology, lipid peroxidation, nuclear factor-κB (NF-κB) activation, and mRNAs for cyclooxygenase-2 (Cox-2) and tumor necrosis factor-α (TNF-α). Endotoxin in plasma was determined. The most severe inflammation and fibrosis were detected in groups 1 and 2, as were the highest levels of endotoxin, lipid peroxidation, activation of NF-κB, and mRNAs for Cox-2 and TNF-α. After the rats were switched to palm oil or MCT, there was marked histological improvement with decreased levels of endotoxin and lipid peroxidation, absence of NF-κB activation, and reduced expression of TNF-α and Cox-2. A diet enriched in saturated fatty acids effectively reverses alcohol-induced necrosis, inflammation, and fibrosis despite continued alcohol consumption. The therapeutic effects of saturated fatty acids may be explained, at least in part, by reduced endotoxemia and lipid peroxidation, which in turn result in decreased activation of NF-κB and reduced levels of TNF-α and Cox-2. Long-term treatment of alcoholic liver disease continues to incorporate vitamins, nutrients, and trace elements (Fulton and McCullough, 1998; McCullough et al., 1998). In fact, the role of specific pharmacological agents remains unproven. Clearly, the development of more effective nutritional or pharmacological therapy will depend on further elucidating the mechanisms that contribute to liver injury. Several lines of investigation indicate that dietary fat can modulate the severity of alcoholic liver injury (Mezey, 1998). In experimental animals, for example, diets enriched with saturated fatty acids protect against alcohol-induced liver injury, whereas diets containing polyunsaturated fatty acids promote liver injury (Nanji and French, 1989; Nanji et al., 1989, 1994a). Saturated fatty acids have also been reported to reverse established alcoholic liver injury (Nanji et al., 1995, 1996, 1997b). Importantly, in previous studies, use of alcohol was discontinued at the time that dietary treatment was initiated. This model represented the alcoholic patient who stopped drinking at the time of hospitalization (French, 1995). Discontinuation of alcohol remains pivotal in the treatment of alcoholic liver disease. Although this goal can frequently be achieved in the short-term, the majority of patients resume alcohol consumption, often with sudden deterioration in liver disease (Pares et al., 1986). Hence, it is important to develop therapeutic strategies that simulate the clinical condition in which alcohol use is continued despite the presence of alcoholic liver disease. Previously, we used the intragastric feeding rat model to study the pathogenesis of alcoholic liver disease (Nanji et al., 1999). In addition to being useful for elucidating mechanisms of injury, this model has been used to evaluate various strategies to prevent or reverse alcoholic liver disease (Nanji et al., 1995, 1997b). The results of previous studies suggest that elevated levels of endotoxin and lipid peroxides in alcohol-fed animals activate nuclear factor-κB (NF-κB), leading to enhanced expression of tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (Cox-2), and proinflammatory cytokines (Nanji et al., 1997a, 1999). In the current study, we investigated whether treatment with dietary saturated fatty acids could reverse established alcoholic liver injury despite continued administration of ethanol. We show that diets enriched in saturated fatty acids improved both histological liver injury and biochemical parameters that have been etiologically linked to liver injury.
(The ferretin levels in the livers of the saturated-fat rats were less than half those of the polyunsaturated fat-rats).
Beef Fat Prevents Alcoholic Liver Disease in the Rat Amin A. Nanji MD, FRCP(C), Charles L.
The amount and type of dietary fat is thought to be important in the pathogenesis of alcoholic liver disease (ALD). We investigated the role of different dietary fats in our rat model for ALD. Liver pathology was evaluated in rats fed ethanol and lard or tallow or corn oil over a period of 2 to 6 months. All experimental animals were pair-fed the same diet as controls except that glucose was isocalorically replaced by ethanol. Rats fed tallow and ethanol developed none of the features of ALD, those fed lard and ethanol developed minimal to moderate disease, rats fed corn oil and ethanol developed the most severe pathology. The degree of histopathological abnormality correlated with the linoleic acid content of fat in the diet (tallow 0.7%, lard 2.5%, corn oil 56.6%). We postulate that linoleic acid facilitates development of ALD and provides an explanation for our previous epidemiological observations. Effect of Dietary Fat on Ito Cell Activation by Chronic Ethanol Intake: A Long-Term Serial Morphometric Study on Alcohol-Fed and Control Rats Hisao Takahashi, Kim Wong, Linda Jui, Amin A. Nanji, Charles S. Mendenhall, Samuel W. French (note: Ito Cells are Hepatic Stellate cells in their normal state. This study is saying that rats fed beef tallow had no loss of Ito cells – that is, no conversion to myofibroblasts – whereas rats fed corn oil went into fibrosis) We studied the effects of long-term ethanol ingestion and dietary fat on Ito cell activation morphometrically in rats. Sixteen pairs of Wistar male rats were divided into two groups, one fed tallow and the other fed corn oil as the source of dietary fat. Each group of rats were pair-fed a nutritional adequate liquid diet containing either corn oil (CF) or tallow (TF) as fat as well as protein and carbohydrate. Half of each group received ethanol, the rest were pair-fed isocaloric amounts of dextrose via an implanted gastric tube for up to 5 months. Morphometric analysis of the change in fat and rough endoplasmic reticulum (RER) of Ito cells was performed on electron micrographs obtained from monthly biopsies including baseline. Ito cell activation was assessed by a decrease in the ratio of fat/RER in Ito cells. The ratio of fat/RER in Ito cells of alcoholic rats fed the CF diet (CFA) gradually decreased. The ratio war found to be lower than in the pair-fed control rats (CFC) at 5 months of feeding. CFA 1.74 ± 0.57, vs. 7.46 ± 2.05, respectlvely, p < 0.05, mean ± se). Ito cell fat also significantly decreased at 5 months of feeding (p < 0.05). The fat/ RER ratio In CFA significantly decreased only subsequent to the development of fatty change, necrosis, and inflammation followed by fibrosis of the liver. In contrast, the TFA rats did not show a significant decrease in the fat/RER ratio in the Ito cells throughout the study, while TFC rats showed an increase in the fat/RER ratio. Minimal pathological changes were observed in the livers of CFC, TFA, and TFC rats. These results indicate that activation of Ito cells at a significant level occurred only late in the course of feeding alcohol after moderate to severe abnormalities in liver histology had developed, although activation may have begun at an earlier time of ethanol feeding. The results indicate that dietary fatty acid composition may be an important factor in the pathogenesis of ethanol-induced Ito cell activation.
