Fomiroid A, a Novel Compound from the Mushroom Fomitopsis nigra, Inhibits NPC1L1-Mediated Cholesterol Uptake via a Mode of Action Distinct from That of Ezetimibe

Abstract

Hypercholesterolemia is one of the key risk factors for coronary heart disease, a major cause of death in developed countries. Suppression of NPC1L1-mediated dietary and biliary cholesterol absorption is predicted to be one of the most effective ways to reduce the risk of hypercholesterolemia. In a screen for natural products that inhibit ezetimibe glucuronide binding to NPC1L1, we found a novel compound, fomiroid A, in extracts of the mushroom Fomitopsis nigra. Fomiroid A is a lanosterone derivative with molecular formula C30H48O3. Fomiroid A inhibited ezetimibe glucuronide binding to NPC1L1, and dose-dependently prevented NPC1L1-mediated cholesterol uptake and formation of esterified cholesterol in NPC1L1-expressing Caco2 cells. Fomiroid A exhibited a pharmacological chaperone activity that corrected trafficking defects of the L1072T/L1168I mutant of NPC1L1. Because ezetimibe does not have such an activity, the binding site and mode of action of fomiroid A are likely to be distinct from those of ezetimibe.

Food Chemistry of Selenium and Controversial Roles of Selenium in Affecting Blood Cholesterol Concentrations

“…First, free cholesterol in the intestinal lumen is transported into the enterocytes by Niemann-Pick C1-like 1 protein (NPC1L1) localized in the brush border membrane . Cholesterol absorption varies between 29 and 80% in the small intestine; therefore, NPC1L1 represents a drug target of cholesterol absorption inhibitors to prevent hypercholesterolemia . Second, acetyl-CoA acyltransferase 2 (ACAT2) converts free cholesterol into cholesteryl ester (CE) in the endoplasmic reticulum (ER), which is then packaged into chylomicrons by microsomal triacylglycerol transport protein (MTP) and absorbed into blood through the lymphatic system .…”

“…55 Cholesterol absorption varies between 29 and 80% in the small intestine; therefore, NPC1L1 represents a drug target of cholesterol absorption inhibitors to prevent hypercholesterolemia. 56 Second, acetyl-CoA acyltransferase 2 (ACAT2) converts free cholesterol into cholesteryl ester (CE) in the endoplasmic reticulum (ER), which is then packaged into chylomicrons by microsomal triacylglycerol transport protein (MTP) and absorbed into blood through the lymphatic system. 57 Inhibition of MTP reduces the formation of very low-density lipoprotein (VLDL) and chylomicrons, which is promising in preventing homozygous familial hypercholesterolemia.…”

C30 and C31 Triterpenoids and Triterpene Sugar Esters with Cytotoxic Activities from Edible Mushroom Fomitopsis pinicola (Sw. Ex Fr.) Krast

“…Thirty-five lanostane triterpenoids and triterpene sugar esters including 13 new compounds ( 1 – 13 ) and twenty-two known analogues ( 14 – 35 ) were isolated from F. pinocola (Figure ). Twenty-two known lanostane triterpenoids were identified to be fomiroid A ( 14 ), 15α-hydroxy-3-oxolanosta-8,24-dien-21-oic acid ( 15 ), pinicolic acid E ( 16 ), ganosinoside A ( 17 ), fomitoside C ( 18 ), 15α-hydroxytrametenolic acid ( 19 ), fomitoside I ( 20 ), 3β-acetoxy-15α-hydroxylanosta-8,24-dien-21-oic acid ( 21 ), 3α-acetoxy-5α-lanosta-8,24-dien-21-oic acid ester β- d -glucoside ( 22 ), fomitoside H ( 23 ), piptolinic acid D ( 24 ), 16α-hydroxy-3-oxolanosta-7,9(11),24-trien-21-oic acid ( 25 ), 3β-hydroxy-16-oxolanosta-7,9(11),24-trien-21-oic acid ( 26 ), 3β- O -acetyl-16α-hydroxydehydrotrametenolic acid ( 27 ), 3β,16α-dihydroxylanosta-7,9(11),24-trien-21-oic acid ( 28 ), 3- epi -dehydropachymic acid ( 29 ), polyporenic acid C ( 30 ), 16α-hydroxy-24-methylene-3-oxolanost-8-en-21-oic acid ( 31 ), 16α-acetoxy-24-methylene-3-oxolanost-8-en-21-oic acid ( 32 ), 3- epi pachymic acid ( 33 ), palustrisoic acid H ( 34 ), and fomitoside K ( 35 ) by comparing their NMR spectroscopic data with compounds reported in the literature. The structure elucidation of 13 new compounds was shown as follows.…”

Inhibitory Effect of Isoliquiritigenin in Niemann-Pick C1-Like 1-Mediated Cholesterol Uptake

“…Hawk tea extract induced transcription downstream of the LDL receptor, thereby inhibiting the uptake of free cholesterol by NPC1L1 [ 35 ]. Fomiroid A interfered with the action of glucosinolates with NPC1L1 and dose-dependently blocked NPC1L1-mediated cholesterol uptake and formation [ 36 ]. Lignans and quercetin inhibited NPC1L1, causing the decrease in intestinal cholesterol absorption [ 37 ].…”