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Knock down activity of PCSK9, increase ldl receptors. What could go wrong?

Here's one I have to wonder about;

Quote:

Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue.
Roubtsova A1, Munkonda MN, Awan Z, Marcinkiewicz J, Chamberland A, Lazure C, Cianflone K, Seidah NG, Prat A.
Author information
Abstract
OBJECTIVE:
Proprotein convertase subtilisin/kexin 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptor (LDLR), and its gene is the third locus implicated in familial hypercholesterolemia. Herein, we investigated the role of PCSK9 in adipose tissue metabolism.

METHODS AND RESULTS:
At 6 months of age, Pcsk9(-/-) mice accumulated ≈80% more visceral adipose tissue than wild-type mice. This was associated with adipocyte hypertrophy and increased in vivo fatty acid uptake and ex vivo triglyceride synthesis. Moreover, adipocyte hypertrophy was also observed in Pcsk9(-/-) Ldlr(-/-) mice, indicating that the LDLR is not implicated. Rather, we show here by immunohistochemistry that Pcsk9(-/-) males and females exhibit 4- and ≈ 40-fold higher cell surface levels of very-low-density lipoprotein receptor (VLDLR) in perigonadal depots, respectively. Expression of PCSK9 in the liver of Pcsk9(-/-) females reestablished both circulating PCSK9 and normal VLDLR levels. In contrast, specific inactivation of PCSK9 in the liver of wild-type females led to ≈ 50-fold higher levels of perigonadal VLDLR.

CONCLUSIONS:
In vivo, endogenous PCSK9 regulates VLDLR protein levels in adipose tissue. This regulation is achieved by circulating PCSK9 that originates entirely in the liver. PCSK9 is thus pivotal in fat metabolism: it maintains high circulating cholesterol levels via hepatic LDLR degradation, but it also limits visceral adipogenesis likely via adipose VLDLR regulation.

Knock out PCSK9, decrease circulating ldl cholesterol. From the abstract, it looks like visceral fat cells--the ones that increase risk of diabetes, insulin resistance etc.-- increase VLDL receptors. VLDL is the lipoprotein that the liver exports triglycerides in, so they're fat rich. It sounds like Pcsk9 inhibition-->increase in visceral fat--> insulin resistance is a possibility to look out for.

Quote:

Because human PCSK9 targets ex vivo human VLDLR15 and binds in vitro mouse VLDLR,16 PCSK9 may also target VLDLR in humans. Whether an increased visceral fat deposition also occurs in humans lacking functional PCSK9 remains to be elucidated. Perigonadal fat is part of what is called the visceral adipose tissue, which correlates directly with obesity-related metabolic disease and coronary heart disease. However, it was recently reported that in obese patients with similar levels of visceral adipose tissue, metabolic complications were more prevalent in those exhibiting higher intrahepatic triglycerides.29 In a clinical perspective, because Pcsk9−/− mice do not develop liver steatosis and are not prone to obesity, the administration of a PCSK9 inhibitor developed for hypercholesterolemia treatment should not result in adverse effects.

Another rabbit hole. liver fat vs. visceral. And it's assumed here that humans will be like the mice--maybe they'll get "wheat" bellies, but not liver fat. A lot of people won't like that anyways.