Intracellular cholesterol transport proteins enhance hydrolysis of HDL-CEs and facilitate elimination of cholesterol into bile

Abstract

This article is available online at http://www.jlr.org cholesterol homeostasis in mammals, including humans. Liver is the central organ for regulating the rate of cholesterol biosynthesis as well as coordinating the elimination of cholesterol via direct secretion into bile or by conversion to more water soluble bile acids. While dietary cholesterol fluxes through the liver in the form of chylomicron remnants taken up via the VLDL or LDL receptor, endogenously synthesized cholesterol is secreted by the liver as part of VLDL and returns to the liver either as IDL or LDL. However, excess cholesterol from nonhepatic peripheral tissues, including artery wall-associated macrophage foam cells, returns to the liver as part of HDL where about 80% of cholesterol is present as cholesteryl esters (CEs) and unesterified or free cholesterol (FC) represents less than 20% of the total HDL cholesterol. HDL-FC is thought to be rapidly and directly secreted into bile without entering the hepatic FC pools (1, 2) and the fate of HDL-associated CEs (HDL-CEs) within a hepatocyte is now beginning to be defined. We identified the neutral CE hydrolase (CEH; gene symbol CES1 in humans and Ces1d in mice) as the enzyme facilitating the intrahepatic hydrolysis of HDL-CE (3) and demonstrated the requirement of SR-BI for this process (3, 4). Gain-of-function (5) and loss-of-function (6) studies further established the role of hepatic CEH in regulating the flux of HDL-CEs to bile, preferentially as bile acids.HDL-derived cholesterol (FC or FC generated after CEH-mediated hydrolysis of HDL-CE) can potentially have multiple fates within the hepatocyte. It can either be resecreted as part of nascent HDL or VLDL following esterification; the two processes that will not facilitate the final elimination of cholesterol from the body. Alternatively, FC can either be directly secreted into bile or converted into bile acids prior to biliary secretion; the two pathways resulting in final elimination of cholesterol from the body. While selective uptake of HDL-CE/FC occurs via SR-BI at the Abstract While HDL-associated unesterified or free cholesterol (FC) is thought to be rapidly secreted into the bile, the fate of HDL-associated cholesteryl esters (HDL-CEs) that represent >80% of HDL-cholesterol, is only beginning to be understood. In the present study, we examined the hypothesis that intracellular cholesterol transport proteins [sterol carrier protein 2 (SCP2) and fatty acid binding protein-1 Due to the lack of enzymes required to degrade the steroid nucleus, balance between synthesis and elimination of cholesterol is crucial to the maintenance of whole body

Ablating both Fabp1 and Scp2/Scpx (TKO) induces hepatic phospholipid and cholesterol accumulation in high fat-fed mice

“…Both Fabp1 [60,63,65] and Scp2/Scpx [72,112,114,121] gene products bind, enhance uptake, facilitate metabolism, and function in removal of cholesterol from the liver into bile. Therefore, the impact of sex and TKO on the hepatic accumulation of cholesterol was determined in HFD fed mice.…”

“…Similarly, SCP2 also facilitates cholesterol transfer from the plasma membrane to the endoplasmic reticulum [29,102] for esterification by ACAT2 [34,86], to mitochondria and peroxisomes for oxidation to steroids [13,14] or bile acids [30,54,81], and to bile canaliculi for biliary excretion [36,54,121]. Thus, it was important to determine the effect of sex and TKO on hepatic expression of cytosolic cholesterol binding/transfer proteins in HFD fed mice.…”

“…FABP1 binds bile acids [60,63,66,67] and enhances transfer/targeting of HDL-derived cholesterol (and cholesteryl ester after hydrolysis) to the bile canaliculus for biliary excretion [36,63,121]. SCP2 enhances cholesterol transfer to mitochondria and peroxisomes for oxidation to bile acids [30,54,81] and to the bile canaliculus for cholesterol biliary excretion [36,54,121]. Therefore, the impact of sex and TKO on hepatic expression of proteins involved in bile acid production and dynamics was determined in HFD fed mice.…”

Triglyceride Metabolism in the Liver

“…SCP-2 ablation also results in alterations in the composition and physical properties of lipid rafts from mice primary hepatocytes, including the enrichment in PL contents (9). Moreover, hepatic SCP-2 and FABP1 act to facilitate hydrolysis of cholesteryl ester molecules associated with high-density lipoprotein (HDL) particles and increasing the biliary secretion of bile acids (270) and cholesterol (92). …”

Bolstering cholesteryl ester hydrolysis in liver: A hepatocyte-targeting gene delivery strategy for potential alleviation of atherosclerosis

“…Primary mouse hepatocytes were isolated by collagenase-perfusion technique as described previously [39]. The hepatocytes were plated in collagen-coated wells in William’s E medium supplemented with heat-inactivated FBS (10 %), insulin (1.5 μM), streptomycin (100 U/mL) and penicillin (100 U/mL).…”