Coordinate Transcriptional Repression of Liver Fatty Acid-binding Protein and Microsomal Triglyceride Transfer Protein Blocks Hepatic Very Low Density Lipoprotein Secretion without Hepatosteatosis

Spann, Nathanael J.; Kang, Sohye; Li, Andrew C.; Chen, Amelia Z.; Newberry, Elizabeth P.; Davidson, Nicholas O.; Hui, Simon T.; Davis, Roger J.

doi:10.1074/jbc.m607148200

Cited by 64 publications

(38 citation statements)

References 66 publications

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“…In the present study, CD36 was unchanged in mice fed a HFD. Prior research has shown that PGC-1␤ interacts with PPAR␣ and activates the transcription of L-FABP (Spann et al, 2006). In the present study, mRNA of these three genes were increased in response to a HFD, suggesting that PGC-1␤ and PPAR␣ may be in part regulating L-FABP induction in mice with reduced (wild-type) and no (Nrf2-null) expression of Nrf2 (Figs.…”

supporting

confidence: 63%

NF-E2-Related Factor 2 Inhibits Lipid Accumulation and Oxidative Stress in Mice Fed a High-Fat Diet

Tanaka¹,

Aleksunes²,

Yeager³

et al. 2008

J Pharmacol Exp Ther

224

151

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NF-E2-related factor 2 (Nrf2) is a transcription factor that is activated by oxidative stress and electrophiles that regulates the expression of numerous detoxifying and antioxidant genes. Previous studies have shown that Nrf2 protects the liver from xenobiotic toxicity; however, whether Nrf2 plays a role in lipid homeostasis in liver is not known. Accordingly, wild-type and Nrf2-null mice were fed a high-fat diet (HFD) for up to 4 weeks. Hepatic gene expression and lipid profiles were analyzed for changes in fatty acid, triglyceride, and cholesterol status. It is interesting to note that HFD reduced the mRNA expression of Nrf2 and its target genes in wild-type mice. The mRNA expression of lipogenic and cholesterologenic transcriptional factors and their target genes, such as sterol regulatory element-binding proteins 1c and 2, fatty acid synthase, acetylCoA carboxylase 1, fatty acid elongase, 3-hydroxy-3-methylglutaryl coenzyme A synthase and reductase, and low-density lipoprotein receptor mRNA expression were higher in Nrf2-null mice compared with wild-type mice after feeding a HFD, suggesting that Nrf2 may suppress these pathways. Hepatic triglycerides and cholesterol levels were not different between genotypes, whereas concentrations of hepatic free fatty acid and malondialdehyde equivalents were higher in Nrf2-null mice compared with wild-type mice 4 weeks after HFD feeding. Overall, these results suggest that Nrf2 inhibits lipid accumulation and oxidative stress in mouse liver after feeding a HFD, probably by interfering with lipogenic and cholesterologenic pathways.

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supporting

confidence: 63%

NF-E2-Related Factor 2 Inhibits Lipid Accumulation and Oxidative Stress in Mice Fed a High-Fat Diet

Tanaka¹,

Aleksunes²,

Yeager³

et al. 2008

J Pharmacol Exp Ther

224

151

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“…These observations, coupled with increased hepatic Mttp mRNA expression and increased hepatic secretion of cholesterol-rich lipoproteins in LD-fed L-Fabp 2/2 mice, suggest that the assembly and secretion of hepatic lipoproteins is substantially modified. Furthermore, these findings provide additional insight into the importance of candidate genes, i.e., Mttp and L-Fabp, shown to undergo coordinate regulation in the context of VLDL secretion (28) in modifying biliary lipid secretion. In this regard, the current findings extend studies showing that mice with liver-specific inactivation of Mttp are protected against diet-induced gallstones (29), while increased hepatic Mttp activity was found in humans with cholesterol gallstone disease (30).…”

Section: Discussionmentioning

confidence: 84%

Increased susceptibility to diet-induced gallstones in liver fatty acid binding protein knockout mice

Xie

Newberry

Kennedy

et al. 2009

Journal of Lipid Research

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Quantitative trait mapping identified a locus colocalizing with L-Fabp, encoding liver fatty acid binding protein, as a positional candidate for murine gallstone susceptibility. When fed a lithogenic diet (LD) for 2 weeks, LFabp 2/2 mice became hypercholesterolemic with increased hepatic VLDL cholesterol secretion. Seventy-five percent of L-Fabp 2/2 mice developed solid gallstones compared with 6% of wild-type mice with an increased gallstone score (3.29 versus 0.62, respectively; P , 0.01). Hepatic free cholesterol content, biliary cholesterol secretion, and the cholesterol saturation index of hepatic bile were increased in LD-fed L-Fabp 2/2 mice. Chow-fed L-Fabp 2/2 mice demonstrated increased fecal bile acid (BA) excretion accompanied by decreased ileal Asbt expression. By contrast, there was an increased BA pool and decreased fecal BA excretion in LD-fed L-Fabp 2/2 mice, associated with increased proximal intestinal Asbt mRNA expression, suggesting that intestinal BA absorption was enhanced in LD-fed L-Fabp 2/2 mice. The increase in biliary BA secretion and enterohepatic pool size in LD-fed L-Fabp 2/2 mice was accompanied by downregulation of Cyp7a1 mRNA and increased intestinal mRNA abundance of Fgf-15, Fxr, and Fabp6. These findings suggest that changes in hepatic cholesterol metabolism and biliary lipid secretion as well as changes in enterohepatic BA metabolism increase gallstone susceptibility in LD fed L-Fabp Gallstone disease is a major health problem in western society, and its attendant complications and comorbidities impose a substantial financial burden on the health care economy (1). Among the factors that predispose to cholesterol cholelithiasis, considerable attention has focused on environmental modifiers, such as obesity, because even in populations at increased genetic risk there appears to be a strong link between gallstone susceptibility and body habitus that may be further modified in a gender-specific manner (2). However, despite recent advances in the mechanisms that link hepatic insulin resistance and gallstone susceptibility (3), there remain many unanswered questions concerning the pathways by which alterations in hepatic lipid metabolism result in biliary cholesterol supersaturation, leading to cholesterol monohydrate crystal formation and eventually the emergence of gallstones (4).Our understanding of the genetic factors that predispose to gallstone formation has been advanced through study of inbred murine crosses in which susceptibility loci have been mapped using diet-induced gallstone formation as a quantitative trait. Using this approach, .23 quantitative trait loci have been mapped, allowing formal evaluation of potential candidate genes [reviewed in (2)]. Among these loci, Liver fatty acid binding protein (L-Fabp) emerged as a positional candidate from a quantitative trait loci near D6Mit123 on chromosome 6 (71.5 Mb, 30 centimorgans) (2, 5). L-Fabp is an abundant cytosolic lipid binding protein expressed in mammalian enterocytes and hepatocytes with a flexible lipid...

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“…Those observations, considered together with earlier fi ndings suggesting that hepatic L-Fabp and Mttp transcription are coordinately regulated ( 14 ), led us to ask whether increasing biliary phospholipid secretion as a result of hepatic Mttp deletion might offset increased canalicular cholesterol secretion in mice with combined deletion ( Mttp-LKO , Mice from four experimental groups were fed a chow diet. Sera were collected after fasting overnight and cholesterol, triglyceride, and ALT were analyzed (see Materials and Methods).…”

Section: Animals and Dietsmentioning

confidence: 99%

Hepatic Mttp deletion reverses gallstone susceptibility in L-Fabp knockout mice

Fung

Newberry

Kennedy

et al. 2014

Journal of Lipid Research

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Coordinate Transcriptional Repression of Liver Fatty Acid-binding Protein and Microsomal Triglyceride Transfer Protein Blocks Hepatic Very Low Density Lipoprotein Secretion without Hepatosteatosis

Cited by 64 publications

References 66 publications

NF-E2-Related Factor 2 Inhibits Lipid Accumulation and Oxidative Stress in Mice Fed a High-Fat Diet

NF-E2-Related Factor 2 Inhibits Lipid Accumulation and Oxidative Stress in Mice Fed a High-Fat Diet

Increased susceptibility to diet-induced gallstones in liver fatty acid binding protein knockout mice

Hepatic Mttp deletion reverses gallstone susceptibility in L-Fabp knockout mice

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