Decreased Hepatic Triglyceride Accumulation and Altered Fatty Acid Uptake in Mice with Deletion of the Liver Fatty Acid-binding Protein Gene

Newberry, Elizabeth P.; Xie, Yan; Kennedy, Susan; Han, Xianlin; Buhman, Kimberly K.; Luo, Jianyang; Gross, Richard W.; Davidson, Nicholas O.

doi:10.1074/jbc.m309377200

Cited by 262 publications

(319 citation statements)

References 31 publications

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“…SCP2 is thought to be present in sufficiently close enough proximity for direct interaction with SR-BI (10) and our earlier results have demonstrated the interaction as well as hydrolysis of SR-BI-delivered HDL-CE by CEH (3). Consistently, SCP2 deficiency failed to increase CEH-mediated hydrolysis of HDL-CE and overexpression of SCP2 in SR-BI / mice also failed to increase hydrolysis is consistent with earlier studies demonstrating SCP2-mediated increase in CYP7A1 activity and bile acid synthesis in vitro (24). SCP2 is also thought to be involved in transport of FC to the endoplasmic reticulum and it is highly likely that by making FC available at the endoplasmic reticulum, SCP2 also increases CYP7A1 activity in vivo and stimulates bile acid synthesis.…”

Section: Discussionsupporting

confidence: 73%

“…The importance of defining the role of SCP2 or FABP1 in regulating the flux of HDL-CE is underscored by the fact that human genetic variations in SCP2 inhibit cholesterol metabolism (20), a phenotype shared with SCP2 / mice (21) and human liver fatty acid binding protein (L-FABP) T94A polymorphism that occurs with a frequency of 32-37% in Caucasians results in hepatic cholesterol accumulation (22). It is noteworthy that deficiency of either SCP2 or FABP1 does not affect the levels of plasma triglyceride, cholesterol, or nonesterified fatty acids in mice (21,23,24).…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Bie

Ghosh

2016

Journal of Lipid Research

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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

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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

Wang

Bie

Ghosh

2016

Journal of Lipid Research

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“…In the mouse, targeted deletion of the L-FABP gene resulted in a reduced rate of LCFA uptake by the liver under conditions of high lipid supply (e.g. intravenous LCFA bolus or prolonged fasting) (18,19). Fasted L-FABP-null mice were characterized by lower hepatic TG synthesis and fatty acid oxidation than wild-type controls (19,20).…”

mentioning

confidence: 99%

Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-dependent

Landrier

Thomas

Grober

et al. 2004

Journal of Biological Chemistry

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Statins are drugs widely used in humans to treat hypercholesterolemia. Statins act by inhibiting cholesterol synthesis resulting in the activation of the transcription factor sterol-responsive element-binding protein-2 that controls the expression of genes involved in cholesterol homeostasis. Statin therapy also decreases plasma triglyceride and non-esterified fatty acid levels, but the mechanism behind this effect remains more elusive. Liver fatty acid-binding protein (L-FABP) plays a role in the influx of long-chain fatty acids into hepatocytes. Here we show that L-FABP is a target for statins. In rat hepatocytes, simvastatin treatment induced L-FABP mRNA levels in a dose-dependent manner. Moreover, L-FABP promoter activity was induced by statin treatment. Progressive 5 -deletion analysis revealed that the peroxisome proliferator-activated receptor (PPAR)-responsive element located at position ؊67/؊55 was responsible for the statin-mediated transactivation of the rat L-FABP promoter. Moreover, treatment with simvastatin and the PPAR␣ agonist Wy14,649 resulted in a synergistic induction of L-FABP expression (mRNA and protein) in rat Fao hepatoma cells. This effect was also observed in vivo in wild-type mice but not in PPAR␣-null animals demonstrating the direct implication of PPAR␣ in L-FABP regulation by statin treatment. Statin treatment resulted in a rise in PPAR␣ mRNA levels both in vitro and in vivo and activated the mouse PPAR␣ promoter in a reporter assay. Altogether, these data demonstrate that L-FABP expression is up-regulated by statins through a mechanism involving PPAR␣. Moreover, PPAR␣ might be a statin target gene. These effects might contribute to the triglyceride/non-esterified fatty acid-lowering properties of statins.Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. The resulting lower intracellular cholesterol concentration after statin treatment leads to a proteolytic activation of the transcription factor sterol responsive element-binding protein-2 (SREBP-2), 1 which up-regulates several genes controlling cholesterol homeostasis, including the LDL receptor (LDLr) (1). Induction of LDLr in the liver enhances clearance of circulating LDL resulting in decreased plasma LDL-cholesterol levels. Statins also increase, at least in part via a PPAR␣-dependent mechanism (2), the level of high density lipoproteins (3, 4). As a consequence, statins improve the blood cholesterol profile and markedly reduce cardiovascular mortality and morbidity in dyslipidemic patients (5-7). Statins also influence plasma TG and NEFA levels in rats and humans (4, 8 -11) through mechanisms not yet fully elucidated. Sustained hepatic clearance of TG-rich very low density lipoproteins by the LDLr (12), statin-dependent up-regulation of the lipoprotein lipase (LPL) gene, and down-regulation of the LPL inhibitor apolipoprotein C-III (13) may all contribute to the TG-lowering effect of statins. By contrast, it is not known if statins control th...

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“…The rate of cytoplasmatic transport of FFA is proportional to the concentration of FABP in the liver (Weisiger, 2002), and inhibition of FABP reduces intracellular FFA transport (Luxon, 1996). Studies with FABP -/-mice showed that these mice exhibited diminished hepatic β-oxidation that was not caused by an impaired oxidative capacity (Atshaves et al, 2010,Newberry et al, 2003. This result lead to the hypothesis, that hepatic FABP acts as a transporter of FFA to the site of β-oxidation (Storch and Thumser, 2010).…”

Section: Iii52 Fatty Acid (Fa) Import and Transportmentioning

confidence: 86%

“…This result lead to the hypothesis, that hepatic FABP acts as a transporter of FFA to the site of β-oxidation (Storch and Thumser, 2010). Additionally, FABP deficient mice show reduced FA uptake and decreased hepatic TG levels when fed a HFD (Newberry et al, 2003,Newberry et al, 2006. The hepatic isoform is FABP1, and qPCR revealed that the expression of this carrier protein was significantly elevated in PI3K p110γ deficient mice fed HFD but not in WT mice on the same diet (Fig 29).…”

Section: Iii52 Fatty Acid (Fa) Import and Transportmentioning

confidence: 92%

The Role of PI3K p110gamma in chronic liver injury

Dostert¹,

Saugspier²,

Dorn³

et al. 2012

Z Gastroenterol

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Decreased Hepatic Triglyceride Accumulation and Altered Fatty Acid Uptake in Mice with Deletion of the Liver Fatty Acid-binding Protein Gene

Abstract: Liver fatty acid-binding protein (L-Fabp

Cited by 262 publications

References 31 publications

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

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

Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-dependent

The Role of PI3K p110gamma in chronic liver injury

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