Peter D has been running a fantastic series on PUFAs and cancer. Lots of references to linoleic acid promoting the growth of hepatoma cells.
"In the lab situation rapid hepatoma tumour growth needs either arachidonic or linoleic acids. The acids must be taken up in to the hepatoma cells, they must be acted on by lipoxygenase to produce 13-hydroxyoctadecadienoic acid, better known as 13-HODE. 13-HODE appears to be the mitogen which promotes rapid cancer growth. 13-HODE looks like a repair signal gone wrong in cancer cells."
Wonderful stuff in line with all the other deleterious effects of excess (seed oil amounts) of linoleate on liver function, and with the benefits of omega 3's.
This passage also caught my eye:
"omega 3 fatty acids, in a G-protein coupled receptor manner, completely turn off the uptake of ALL fatty acids in to hepatoma cells. If, and it's quite a big "if", the same effects apply to hepatocytes as well as hepatoma cells, we then have a very straightforward mechanism for the protective effects of omega 3 fish oils on hepatic lipidosis."
(or for that matter, steatosis).
This interests me because, in Hep C research, HCV can only be cultured in hepatoma cells. You can't culture it in normal hepatocytes. And this provides an answer to an old question - why do viruses cause cancer? What's the benefit, given the risk of killing the host? Because, there is something about the cancer phenotype of a cell that makes the cell a better host to the virus. Obviously it doesn't want to push carcinogenesis all the way (which is why only a small minority of chronic HCV cases end up as HCC), but it does want to tweak the cell a little in that direction. Hence activities like sequestering selenium. Better not give that virus-infected cell too much linoleate to play with.
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In the middle of this discussion, Purposelessness dropped this 2008 mouse paper:
This is great science thinking about the obesity epidemic. Why are high-carb diets only generally productive of obesity when linoleate is added, and not, say, in Kitava (where most fat comes from coconut and some from fish?). If it's the linoleate, how come low-carb dieters loose weight on cupfuls of nuts and olive oil - or even canola oil - with everything?
The effect of dietary fat on human health is not solely a matter of quantity but depends also on the nature of the fatty acids. The current recommendation is to replace saturated fat by polyunsaturated fatty acids (PUFAs).5 Today, more than 85% of the total dietary PUFA intake in Western diets is n-6 PUFAs, mainly linoleic acid, a precursor of arachidonic acid, whereas the consumption of n-3 PUFAs has declined (1). Since the high intake of n-6 has been associated with childhood obesity, concerns regarding this matter have been raised (2). However, animal studies have yielded conflicting results, with some studies demonstrating that a diet enriched in n-6 PUFAs decreases adipose tissue mass (3, 4), whereas others have associated intake of n-6 PUFAs with an increased propensity for obesity (5-7).
So, we have a paradox. And a solution.
In the present study, we present data that reconcile and explain the disparate effects of n-6 PUFAs on adipocyte differentiation in vitro and in vivo. We demonstrate that cAMP signaling plays a pivotal role controlling the production of antiadipogenic prostaglandins. In vivo, the obesigenic action of n-6 PUFAs is determined by the balance between dietary carbohydrates and protein. A high carbohydrate/protein ratio translated into a high plasma insulin/glucagon ratio, and in this setting, dietary n-6 PUFAs promoted strongly adipose tissue expansion. Conversely, a high protein/carbohydrate ratio translated into a high plasma glucagon/insulin ratio and enhanced cAMP-dependent signaling. In this setting, COX-mediated prostaglandin synthesis was enhanced, and dietary n-6 PUFAs decreased white adipose tissue mass.
Don't try this last bit at home; those prostaglandins might not be liver-friendly, but you can do much the same job with omega 3s.
This bit is for all the calorie nerds:
The decreased obesigenic action ofn-6 PUFAs in mice fed a protein-rich diet did not result from increased dissipation of energy by uncoupled respiration but rather reflected increased energy expenditure in relation to gluconeogenesis and urea formation.
Phew, we didn't break the laws of thermodynamics, so the CICO police are not after us.
We observed a remarkable difference in feed efficiency between mice fed the protein-enriched versus the carbohydrate-enriched diet. In the high protein group, 467.8 kcal were needed to produce a weight gain of 1 g, whereas the high carbohydrate group only needed 67.8 kcal to produce the same weight gain, which almost exclusively represented an increase in adipose tissues. Increased cAMP signaling is known to induce adaptive thermogenesis by inducing expression of PGC-1α and UCP1 in brown adipose tissue (30), but the fact that heat production and oxygen consumption as well as expression of UCP1 in intracapular brown adipose tissue were similar in the two groups of mice indicated that decreased feed efficiency of the protein group was not due to increased uncoupled respiration. Furthermore, no increase in genes involved in fatty acid oxidation in muscle and liver was observed in the mice fed the protein-enriched diet, and the total physical activity of the carbohydrate and the protein group did not differ. Expression of UCP1 and genes involved in β-oxidation was, however, induced in the inguinal fat pad, but the relatively low expression of these genes compared with interscapular brown adipose tissue suggested that such a contribution to whole body metabolism was limited.
Oh no, not DNL too, I though that was all debunked, sorry folks
A hallmark of PUFA action is the ability to increase catabolism by enhancing ketogenesis and peroxisomal and mitochondrial fatty acid oxidation and to suppress expression of genes involved in lipogenesis in rodents (36). It is worth noting that the hepatic expression of rate-limiting enzymes involved in fatty acid catabolism was similar in mice fed corn oil supplemented with protein and sucrose. In contrast, expression of genes involved in lipogenesis was significantly lower in liver of mice fed corn oil and protein compared with corn oil and sucrose. Thus, despite high dietary intake of fatty acids, expression of genes involved in de novo synthesis of fatty acid continued when dietary corn oil was combined with sucrose.
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In conclusion:
In conclusion, we have shown that the adipogenic potential of n-6 PUFAs is modulated by cAMP signaling both in vivo and in vitro. Differences in culture conditions and feeding regimes affecting the glucagon/insulin ratio provide an explanation for the contradictory results published in the literature. Today's diets are abundant in n-6 fatty acids from vegetable oils (corn, sunflower, safflower, and soybeans) that are used in industrially prepared food. In addition, industrially produced animal feed is also rich in grains containing n-6 PUFAs, leading to meat enriched in n-6 PUFAs at the expense of n-3 fatty acids (39). n-6 PUFAs, predominantly linoleic acid, are now the predominant source of PUFAs in Western diets (23). PUFAs have been considered less harmful to human health than saturated fat, and substitution of saturated fat with PUFAs in general has been recommended by dieticians. If the background diet determines the adipogenic potential of n-6 PUFAs also in humans, this is of great concern, since the intake of refined sugars from sources such as soft drinks has increased dramatically during recent decades (40).
Background diet? Insulin-elevating carbohydrate. Result? Adiposity. Culprit? Linoleic acid.
I like this model because it provides a face-saving formula for many factions currently locked in bitter dispute, and because it seems to reflect the various realities we see around us. It's certainly not my job to help solve the obesity epidemic, but every now and then one can't help but take an interest, because the science gets good.
What will happen when fat, with normal protein, is substituted for carbohydrate? Less protein metabolism energy loss, different body composition, less COX-mediated prostaglandin but maybe the cAMP will still be elevated. On to the next experiment then.
Now about that proposed Kiwi saturated fat tax, supposed to increase our PUFA intake without decreasing our intake of carbs?
There's a thing called Unintended Consequences. I like this example, reminds me of the good old days:
Theobald Mathew's temperance campaign in 19th-century Ireland (in which thousands of people vowed never to drink alcohol again) led to the consumption of diethyl ether, an intoxicant much more dangerous due to its high flammability, by those seeking to become intoxicated without breaking the letter of their pledge.
(Ether in Ireland, from Psychology Today; Ether in Silesia, a fascinating J. Medical History article from PubMed)
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The only thing that really worried me was the ether. There is nothing in the world more helpless and irresponsible and depraved than a man in the depths of an ether binge
- Hunter S. Thompson
"In the lab situation rapid hepatoma tumour growth needs either arachidonic or linoleic acids. The acids must be taken up in to the hepatoma cells, they must be acted on by lipoxygenase to produce 13-hydroxyoctadecadienoic acid, better known as 13-HODE. 13-HODE appears to be the mitogen which promotes rapid cancer growth. 13-HODE looks like a repair signal gone wrong in cancer cells."
Wonderful stuff in line with all the other deleterious effects of excess (seed oil amounts) of linoleate on liver function, and with the benefits of omega 3's.
This passage also caught my eye:
"omega 3 fatty acids, in a G-protein coupled receptor manner, completely turn off the uptake of ALL fatty acids in to hepatoma cells. If, and it's quite a big "if", the same effects apply to hepatocytes as well as hepatoma cells, we then have a very straightforward mechanism for the protective effects of omega 3 fish oils on hepatic lipidosis."
(or for that matter, steatosis).
This interests me because, in Hep C research, HCV can only be cultured in hepatoma cells. You can't culture it in normal hepatocytes. And this provides an answer to an old question - why do viruses cause cancer? What's the benefit, given the risk of killing the host? Because, there is something about the cancer phenotype of a cell that makes the cell a better host to the virus. Obviously it doesn't want to push carcinogenesis all the way (which is why only a small minority of chronic HCV cases end up as HCC), but it does want to tweak the cell a little in that direction. Hence activities like sequestering selenium. Better not give that virus-infected cell too much linoleate to play with.
In the middle of this discussion, Purposelessness dropped this 2008 mouse paper:
cAMP-dependent Signaling Regulates the Adipogenic Effect of n-6 Polyunsaturated Fatty Acids
This is great science thinking about the obesity epidemic. Why are high-carb diets only generally productive of obesity when linoleate is added, and not, say, in Kitava (where most fat comes from coconut and some from fish?). If it's the linoleate, how come low-carb dieters loose weight on cupfuls of nuts and olive oil - or even canola oil - with everything?
The effect of dietary fat on human health is not solely a matter of quantity but depends also on the nature of the fatty acids. The current recommendation is to replace saturated fat by polyunsaturated fatty acids (PUFAs).5 Today, more than 85% of the total dietary PUFA intake in Western diets is n-6 PUFAs, mainly linoleic acid, a precursor of arachidonic acid, whereas the consumption of n-3 PUFAs has declined (1). Since the high intake of n-6 has been associated with childhood obesity, concerns regarding this matter have been raised (2). However, animal studies have yielded conflicting results, with some studies demonstrating that a diet enriched in n-6 PUFAs decreases adipose tissue mass (3, 4), whereas others have associated intake of n-6 PUFAs with an increased propensity for obesity (5-7).
So, we have a paradox. And a solution.
In the present study, we present data that reconcile and explain the disparate effects of n-6 PUFAs on adipocyte differentiation in vitro and in vivo. We demonstrate that cAMP signaling plays a pivotal role controlling the production of antiadipogenic prostaglandins. In vivo, the obesigenic action of n-6 PUFAs is determined by the balance between dietary carbohydrates and protein. A high carbohydrate/protein ratio translated into a high plasma insulin/glucagon ratio, and in this setting, dietary n-6 PUFAs promoted strongly adipose tissue expansion. Conversely, a high protein/carbohydrate ratio translated into a high plasma glucagon/insulin ratio and enhanced cAMP-dependent signaling. In this setting, COX-mediated prostaglandin synthesis was enhanced, and dietary n-6 PUFAs decreased white adipose tissue mass.
Don't try this last bit at home; those prostaglandins might not be liver-friendly, but you can do much the same job with omega 3s.
This bit is for all the calorie nerds:
The decreased obesigenic action ofn-6 PUFAs in mice fed a protein-rich diet did not result from increased dissipation of energy by uncoupled respiration but rather reflected increased energy expenditure in relation to gluconeogenesis and urea formation.
Phew, we didn't break the laws of thermodynamics, so the CICO police are not after us.
We observed a remarkable difference in feed efficiency between mice fed the protein-enriched versus the carbohydrate-enriched diet. In the high protein group, 467.8 kcal were needed to produce a weight gain of 1 g, whereas the high carbohydrate group only needed 67.8 kcal to produce the same weight gain, which almost exclusively represented an increase in adipose tissues. Increased cAMP signaling is known to induce adaptive thermogenesis by inducing expression of PGC-1α and UCP1 in brown adipose tissue (30), but the fact that heat production and oxygen consumption as well as expression of UCP1 in intracapular brown adipose tissue were similar in the two groups of mice indicated that decreased feed efficiency of the protein group was not due to increased uncoupled respiration. Furthermore, no increase in genes involved in fatty acid oxidation in muscle and liver was observed in the mice fed the protein-enriched diet, and the total physical activity of the carbohydrate and the protein group did not differ. Expression of UCP1 and genes involved in β-oxidation was, however, induced in the inguinal fat pad, but the relatively low expression of these genes compared with interscapular brown adipose tissue suggested that such a contribution to whole body metabolism was limited.
Oh no, not DNL too, I though that was all debunked, sorry folks
A hallmark of PUFA action is the ability to increase catabolism by enhancing ketogenesis and peroxisomal and mitochondrial fatty acid oxidation and to suppress expression of genes involved in lipogenesis in rodents (36). It is worth noting that the hepatic expression of rate-limiting enzymes involved in fatty acid catabolism was similar in mice fed corn oil supplemented with protein and sucrose. In contrast, expression of genes involved in lipogenesis was significantly lower in liver of mice fed corn oil and protein compared with corn oil and sucrose. Thus, despite high dietary intake of fatty acids, expression of genes involved in de novo synthesis of fatty acid continued when dietary corn oil was combined with sucrose.
In conclusion:
In conclusion, we have shown that the adipogenic potential of n-6 PUFAs is modulated by cAMP signaling both in vivo and in vitro. Differences in culture conditions and feeding regimes affecting the glucagon/insulin ratio provide an explanation for the contradictory results published in the literature. Today's diets are abundant in n-6 fatty acids from vegetable oils (corn, sunflower, safflower, and soybeans) that are used in industrially prepared food. In addition, industrially produced animal feed is also rich in grains containing n-6 PUFAs, leading to meat enriched in n-6 PUFAs at the expense of n-3 fatty acids (39). n-6 PUFAs, predominantly linoleic acid, are now the predominant source of PUFAs in Western diets (23). PUFAs have been considered less harmful to human health than saturated fat, and substitution of saturated fat with PUFAs in general has been recommended by dieticians. If the background diet determines the adipogenic potential of n-6 PUFAs also in humans, this is of great concern, since the intake of refined sugars from sources such as soft drinks has increased dramatically during recent decades (40).
Background diet? Insulin-elevating carbohydrate. Result? Adiposity. Culprit? Linoleic acid.
I like this model because it provides a face-saving formula for many factions currently locked in bitter dispute, and because it seems to reflect the various realities we see around us. It's certainly not my job to help solve the obesity epidemic, but every now and then one can't help but take an interest, because the science gets good.
What will happen when fat, with normal protein, is substituted for carbohydrate? Less protein metabolism energy loss, different body composition, less COX-mediated prostaglandin but maybe the cAMP will still be elevated. On to the next experiment then.
Now about that proposed Kiwi saturated fat tax, supposed to increase our PUFA intake without decreasing our intake of carbs?
There's a thing called Unintended Consequences. I like this example, reminds me of the good old days:
Theobald Mathew's temperance campaign in 19th-century Ireland (in which thousands of people vowed never to drink alcohol again) led to the consumption of diethyl ether, an intoxicant much more dangerous due to its high flammability, by those seeking to become intoxicated without breaking the letter of their pledge.
(Ether in Ireland, from Psychology Today; Ether in Silesia, a fascinating J. Medical History article from PubMed)
The only thing that really worried me was the ether. There is nothing in the world more helpless and irresponsible and depraved than a man in the depths of an ether binge
- Hunter S. Thompson