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Thursday 14 June 2012

HCV, Fructose and Fox01

Here's a bit of corroborating evidence on the wisdom of restricting fructose in Hep C, and the possibility that HCV might create a fructose sensitivity predisposing towards insulin resistance and type 2 diabetes.

Fox01 is a transcription factor involved in the response to insulin; it governs both lipogenesis (the conversion of carbohydrate to fats) and gluconeogenesis (the production of glucose) in the liver. These are both ways in which excess energy can be sent out from the liver, or stored there in a stable form.

HCV core protein increases Fox01 activity via oxidative stress, which causes the transcription factor to be retained in the nucleus;

Fructose increases Fox01 activity by increasing its production;

Thus there is potential for a synergistic effect of HCV plus fructose to disregulate insulin response, triglycerides, and blood sugar, beyond that of either acting independently.
Further, as HCV core protein causes Fox01 retention as a result of mitochondrial superoxide production (HCV core protein inhibits complex 1 in the mitochondrial respiratory chain), this can also be ameliorated by supplementation of mitochondrial antioxidants; Co-enzyme q10 (or ubiquinol), manganese, tocopherol and selenium; zinc, copper, carnitine, and phospholipids.

This is consistent with the trials of MitoQ as a hepatoprotectant in Hep C.

Furthermore, as can be seen from the fructose reference above, PPAR-alpha can antagonise Fox01: PPAR-alpha is upregulated in carbohydrate, or calorie, restriction.

"The data indicate that PPARĪ± plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARĪ± stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues."

This suggests ketogenic dieting and/or intermittent fasting as strategies that can be used to clear liver fat and normalise blood sugar regulation.

For example:

"The Salk study found the body stores fat while eating and starts to burn fat and breakdown cholesterol into beneficial bile acids only after a few hours of fasting. When eating frequently, the body continues to make and store fat, ballooning fat cells and liver cells, which can result in liver damage. Under such conditions the liver also continues to make glucose, which raises blood sugar levels. Time-restricted feeding, on the other hand, reduces production of free fat, glucose and cholesterol and makes better use of them. It cuts down fat storage and turns on fat burning mechanisms when the animals undergo daily fasting, thereby keeping the liver cells healthy and reducing overall body fat.

The daily feeding-fasting cycle activates liver enzymes that breakdown cholesterol into bile acids, spurring the metabolism of brown fat - a type of "good fat" in our body that converts extra calories to heat. Thus the body literally burns fat during fasting. The liver also shuts down glucose production for several hours, which helps lower blood glucose. The extra glucose that would have ended up in the blood - high blood sugar is a hallmark of diabetes - is instead used to build molecules that repair damaged cells and make new DNA. This helps prevent chronic inflammation, which has been implicated in the development of a number of diseases, including heart disease, cancer, stroke and Alzheimer's. Under the time-restricted feeding schedule studied by Panda's lab, such low-grade inflammation was also reduced. "

When we say restrict fructose - which is surely the simplest way to avoid over-activating Fox01 - what is meant?

Dietary sources that are highest in fructose are sugar, high-fructose corn syrup, and fruit juice (especially apple or grape juice concentrate). Agave, honey, and dried or tinned fruit are also high in fructose. Drink and snack sweeteners are especially problematic because they tend to be consumed between meals; thus they not only increase fructose exposure, but also support the "constant feeding" model that is the opposite of intermittent fasting (or traditional, scheduled eating), and that leads to fatty liver, high triglycerides, and blood sugar disregulation.
Fruit, while an important source of fructose, is less problematic because the amount in a serving is small and the presence of fibre, minerals, vitamin C and polyphenols provides benefits (for example, naringenin in grapefruit and other citrus fruits activates PPAR-alpha). It is recommended that two servings of fresh, unsweetened fruit be eaten daily.
Sugar in small amounts as a normal culinary ingredient, eaten only at meal times (for example in sauce or relish, or dried fruit in curries) is probably not an issue; but the use of sweetened drinks and snacks, including commercial fruit juices, icecream, and meusli bars, between meals is the sort of thing that should be discouraged...

Your grandparents were right.