Retatrutide's lipid lowering effect independent of LDLR

By this point we've all heard about Reta/Retatrutide.

Safe to say by now it's also predominately known as a tool that simply helps with fat loss. Sometimes it doesn't even go beyond that for people to jump on board.

There are some other really awesome mechanisms that are less spoken about when it comes to glucagon agonism, and that's the effect on lipid lowering via the ANGPTL 3/8 protein.

Let's dive in:

How is it actually lowering cholesterol?

It's via the angiopoietin-like protein (ANGPTL 3/8).

There are eight of these angiopoietin-like proteins (ANGPTL 1-8), and for lipid metabolism, three matter:

ANGPTL3: secreted by the liver, circulates systemically. It inhibits LPL in oxidative tissues (muscle, heart) and inhibits EL on the endothelium

ANGPTL4: secreted by adipose, liver, and heart. Inhibits LPL primarily in adipose during fasting. Inactivated by ANGPTL8 during feeding.
ANGPTL8: produced by liver and adipose. Acts as a molecular switch and pairs with ANGPTL4 to activate it forming (ANGPTL3/8).

How ANGPTL 3/8 is regulated

Fed state (insulin is high). ANGPTL8 rises in liver & adipose. Liver ANGPTL8 binds with ANGPTL3 and creates the combo 3/8. This combination inhibits LPL in oxidative tissues (muscle, heart). Ultimately dietary fat is routed to adipose for storage
Fasted state (glucagon high) ANGPTL8 falls and ANGPTL4 suppresses LPL in adipose. ANGPTL3/8 also falls, freeing up LPL in muscle & heart, ultimately mobilizing fat into oxidative tissues for burning.

Insulin induces hepatic ANGPTL3/8 secretion and glucagon suppresses it. This is why Reta, via the glucagon agonism, pulls on this system.

What LPL does:

It hydrolyzes (breaks down) stored triglycerides inside chylomicrons and VLDL particles. It releases free fatty acids that are taken up by the underlying tissue. When LPL is freed (ANGPTL3/8 low): triglyceride rich lipoproteins clear faster, plasma triglycerides fall, and remnant processing accelerates.

What EL does:

Acts as a phospholipase on the lipid coats of LDL and HDL particles. Importantly, EL drives the alternative VLDL-remnant processing pathway: VLDL remnants get stripped of their phospholipid coat by EL, then converted to lipid-depleted remnants, and are cleared from circulation through non-LDLR routes. This ultimately depletes the LDL precursor pool, and this is how circulating LDL-c drops without ever touching an LDL receptor.

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