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Thursday, 17 October 2013

PCSK9, Alirocumab, and why high linoleic acid intakes increase vulnerability to Hepatitis C

In ancient times, those suffering from ye surfeit of choleric humours were prescribed a purgative compounded of tincture of statin. Modern science, from its evidence-based wisdom, has compounded a new elixir by the name of Alirocumab (the drug being named after its father, one of the Legions of Satan listed in the Enochian Book of Revelation).

Music: Rasputina, "The Signs of the Zodiac"
Do you believe in the Signs of the Zodiac?
Haven't you found that the systems for
Planning always fail?

Can you avoid what gave Daddy his heart attack?
Have you tried everything, anything
All to no avail?

I know what you need.
This will really work.
In ancient times, if you were sick
They make you bleed.
Oh, honey I know it hurts.

Alirocumab has the remarkable property of reducing cholesterol by 47.2%. At this rate cholesterol will soon be as rare as smallpox. Alirocumab is a fortnightly-injectible antibody that inhibits a protein called PCSK9, which regulates hepatic lipoprotein uptake by degrading LDL receptors and preventing them from being re-used. Less PCSK9, more LDL receptors, more cholesterol, lipids etc. going into hepatocytes. What could possibly go wrong?

Human PCSK9 is known to enhance the degradation of membrane-bound receptors such as the hepatocyte low-density lipoprotein receptor (LDLR), ApoER2, and very low-density lipoprotein receptor. Because the LDLR is suspected to be involved in hepatitis C virus (HCV) entry, we also tested whether PCSK9 can affect the levels of CD81, a major HCV receptor. Interestingly, stable expression of PCSK9 or a more active membrane-bound form of the protein (PCSK9-ACE2) resulted in a marked reduction in CD81 and LDLR expression. Therefore, we analyzed the antiviral effect of PCSK9 in vitro using the HCV genotype 2a (JFH1) virus. The results clearly demonstrated that cells expressing PCSK9 or PCSK9-ACE2, but not the ACE2 control protein, were resistant to HCV infection. Furthermore, addition of purified soluble PCSK9 to cell culture supernatant impeded HCV infection in a dose-dependent manner. As expected, HuH7 cells expressing PCSK9-ACE2 were also resistant to infection by HCV pseudoparticles. In addition, we showed that CD81 cell surface expression is modulated by PCSK9 in an LDLR-independent manner. Finally, in the liver of single Pcsk9 and double (Pcsk9 + Ldlr) knockout mice, both LDLR and/or CD81 protein expression levels were significantly reduced, but not those of transferrin and scavenger receptor class B type 1. Conclusion: Our results demonstrate an antiviral effect of the circulating liver PCSK9 on HCV in cells and show that PCSK9 down-regulates the level of mouse liver CD81 expression in vivo. Therefore, we propose that the plasma level and/or activity of PCSK9 may modulate HCV infectivity in humans. (Hepatology 2009.)

So lowering cholesterol with Alirocumab looks set to increase the spread of hepatitis C. But what else decreases PCSK9? If PCSK9 increases LDL (the "bad" cholesterol), does saturated fat increase PCSK9?
The answers may surprise you.

Plasma PCSK9 concentrations vary minimally in response to a short term high-fat diet and they are not accompanied with changes in cholesterolemia upon high-fructose diet. Short-term high-fructose intake increased plasma PCSK9 levels, independent on cholesterol synthesis, suggesting a regulation independent of SREBP-2. Upon this diet, PCSK9 is associated with insulin resistance, hepatic steatosis and plasma triglycerides.
We previously showed that hepatic PCSK9 expression is subjected to nutritional regulation, being decreased upon fasting and increased following re-feeding with a high carbohydrate diet in rodents[14]. Insulin increases hepatic PCSK9 expression both in vitro in hepatocytes and in vivo in mice[14]. Conversely, PCSK9 is repressed by glucagon in rat liver [16]. Accordingly, fasting, but not a ketogenic diet, reduces plasma PCSK9 concentrations in healthy volunteers, with a ≈ 20–35% decrease after 18 h [17,18]. However, so far there are only two reports that describe a dietary modulation of PCSK9 in human. The Mediterranean diet [19] and n-6 PUFAs [20] have been shown to decrease plasma PCSK9 concentrations by ≈ 12% and 13%, respectively.

And again:

PCSK9 (P = 0.001), TNF receptor-2 (P < 0.01), and IL-1 receptor antagonist (P = 0.02) concentrations were lower during the PUFA diet, whereas insulin (P = 0.06) tended to be higher during the SFA diet. In compliant subjects (defined as change in serum linoleic acid), insulin, total/HDL-cholesterol ratio, LDL cholesterol, and triglycerides were lower during the PUFA diet than during the SFA diet (P < 0.05).
(Note that this was not a high-fat diet "
The participants were instructed (unblinded) to change the quality of their dietary fat without altering their intakes of total fat and the type and amount of carbohydrates and protein. The participants were encouraged not to change their physical activity or their fish and alcohol intakes during the study. Some key food items were provided: the PUFA group received foods rich in n−6 linoleic acid, ie, scones (baked-on sunflower oil), margarine, sunflower oil, and sunflower seeds, and the SFA group received scones (baked-on butter) and butter.")

Taking this all together - rather messy and unsatisfactory though it may be - it appears that saturated fat does not significantly increase PCSK9 levels, nor does protein (insulin and glucagon in balance), but that high fructose/carbohydrate and insulin do. High linoleic acid decreases PCSK9.

Now, however desirable elevated PCSK9 may be to people with HCV, we don't want to achieve it with elevated carbohydrate and insulin because this will switch off PPAR-alpha, the other antiviral protein

File:Human hepatocyte PPARalpha transcriptome.png
The PPAR-alpha transcriptome in a human hepatocyte

Your classic LCHF Paleo diet is designed to maximise PPAR-alpha while leaving PCSK9 intact.
And that surfeit of choleric humours? It looks very much like the fructose, carbohydrate and insulin axis was responsible for any PCSK9 contribution to that.
Will people henceforth be dosing with Aloricumab so that they can enjoy sweet and starchy treats without alarming the doctors who audit their lipid returns?
This is the world we live in.

Anyway here is The Strangest Book in the World, accompanied by some rather wonderful music

And Part 2:


Puddleg said...

To be fair, statins come out of this study pretty well (though with odd injunctions around the effect of education on the HR)
What doesn't survive is the lipid hypothesis.
High TC makes no difference to statin and is protective by itself.

For TC, the mortality was significantly lower in the TC groups 5–5.99 mmol/L and 6–7.99 mmol/L, in both sexes and in all age groups compared with the group with TC < 5 mmol/L. For the groups with the highest TC level (≥ 8 mmol/L), the mortality becomes significantly lower in the oldest age group compared with the group with the lowest TC. For HDL-C in females, there was a decreased mortality in all ages in the groups with a HDL-C above 1 mmol/L. In males there was a decreased mortality in the HDL-C groups 1–1.49 and 1.5–1.99 mmol/L in all age groups, but the highest HDL-C group only had a decreased mortality in the age group > 70 years.

For triglycerides, the findings were almost the opposite. In females there was an increased mortality in the age group 50–60 years in all groups with a triglyceride level above 1 mmol/L. In the age group 60–70 years, there was an increased mortality in the group with the highest triglyceride level in both sexes.

There was a significant interaction between statin prescription and TC in both sexes in the age group 60–70 years, meaning that the frequency of statin use, as expected, was higher in the groups with higher TC. Furthermore, there was a significant interaction between HDL-C and statin use in females aged 60–70 years. No other interactions were found and the analyses regarding TC and HDL-C levels were adjusted for this interaction. Use of statin (after test date) and above 12 years of education provided a survival benefit that was significant in almost all age and lipoprotein/triglyceride groups in both sexes.

Unknown said...

Alirocumab is a novel PCSK9 inhibitor that is approved by FDA on July 24, 2015 for the treatment of patients with high cholesterol whose cholesterol is not controlled by diet and statin therapy. Alirocumab