Protection against Western diet–induced obesity and hepatic steatosis in liver fatty acid–binding protein knockout mice

Newberry, Elizabeth P.; Xie, Yan; Kennedy, Susan; Luo, Jianyang; Davidson, Nicholas O.

doi:10.1002/hep.21369

Cited by 179 publications

(201 citation statements)

References 47 publications

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“…In addition to a potential role in intracellular FA trafficking, L-FABP has been suggested to play a role in cell division (23), to serve as a cytosolic reservoir for high levels of unesterified FA (18), and to interact with nuclear hormone receptors, perhaps delivering specific ligands (24). Finally, and of particular relevance to the present studies, it has been reported recently that mice null for L-FABP exhibit impaired intestinal TAG secretion (25).…”

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confidence: 52%

“…Newberry et al (25) found that L-FABP gene-disrupted mice fed a high fat diet retained more TAG in their intestines, relative to WT mice. Furthermore, L-FABP KO mice given the lipoprotein lipase inhibitor, tyloxapol, had a reduction in their serum TAG on being fed a lipid bolus, suggesting a reduced chylomicron output from the intestine as compared with normal mice.…”

Section: Discussionmentioning

confidence: 99%

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Liver Fatty Acid-binding Protein Initiates Budding of Pre-chylomicron Transport Vesicles from Intestinal Endoplasmic Reticulum

Neeli

Siddiqi

Mahan³

et al. 2007

Journal of Biological Chemistry

105

102

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The rate-limiting step in the transit of absorbed dietary fat across the enterocyte is the generation of the pre-chylomicron transport vesicle (PCTV) from the endoplasmic reticulum (ER). This vesicle does not require coatomer-II (COPII) proteins for budding from the ER membrane and contains vesicle-associated membrane protein 7, found in intestinal ER, which is a unique intracellular location for this SNARE protein. We wished to identify the protein(s) responsible for budding this vesicle from ER membranes in the absence of the requirement for COPII proteins. We chromatographed rat intestinal cytosol on Sephacryl S-100 and found that PCTV budding activity appeared in the low molecular weight fractions. Additional chromatographic steps produced a single major and several minor bands on SDS-PAGE. By tandem mass spectroscopy, the bands contained both liver and intestinal fatty acid-binding proteins (L-and I-FABP) as well as four other proteins. Recombinant proteins for each of the six proteins identified were tested for PCTV budding activity; only L-FABP and I-FABP (23% the activity of L-FABP) were active. The vesicles generated by L-FABP were sealed, contained apolipoproteins B48 and AIV, were of the same size as PCTV on Sepharose CL-6B, and by electron microscopy, excluded calnexin and calreticulin but did not fuse with cis-Golgi nor did L-FABP generate COPII-dependent vesicles. Gene-disrupted L-FABP mouse cytosol had 60% the activity of wild type mouse cytosol. We conclude that L-FABP can select cargo for and bud PCTV from intestinal ER membranes.During intestinal lipolysis of a fat-containing meal, 2 mol of fatty acid (FA) 4 are produced for every mole of triacylglycerol (TAG) hydrolyzed. These FA and the remaining sn-2-monoacylglycerol are absorbed across the enterocyte apical plasma membrane. Absorption of the FA is thought to occur, at least in part, via specific membrane proteins. FATP4, which is highly expressed at the apical surface of the enterocyte, was shown to increase FA uptake following overexpression, and antisense oligonucleotide knockdown of FATP4 expression reduced FA uptake (1). FABPpm, which was first identified in jejunal microvillus membranes, may also be involved in FA uptake, as anti-FABPpm antibodies have been found to inhibit uptake (2-4). CD36 has been shown to be important for FA uptake into muscle and adipose tissues (5, 6) and may also play a role in intestinal FA transport (7). 5 CD36 is also important for intestinal TAG synthesis and subsequent TAG export from the intestine (8). Kinetic experiments have shown that in addition to protein-mediated transport, a diffusional mechanism for FA uptake by the enterocyte exists as well (9).Once inside the intestinal absorptive cell, the FA are largely bound to intracellular fatty acid-binding proteins (FABP), and the majority are rapidly converted into TAG (10) for subsequent export from the cell as the major component of intestinal lipoproteins, chylomicrons, and very low density lipoproteins.The absorptive enterocyte contains high levels...

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mentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Liver Fatty Acid-binding Protein Initiates Budding of Pre-chylomicron Transport Vesicles from Intestinal Endoplasmic Reticulum

Neeli

Siddiqi

Mahan³

et al. 2007

Journal of Biological Chemistry

105

102

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“…The Noc Ϫ/Ϫ mice show similarity to one lean mouse model, the L-Fabp-deficient mouse (28). L-Fabp Ϫ/Ϫ mice are resistant to weight gain and fat accumulation in the liver and also develop changes in glucose homeostasis on a high-fat diet.…”

Section: Discussionmentioning

confidence: 97%

Loss of Nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity

Green

Douris

Kojima

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

202

201

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The mammalian circadian system consists of a central oscillator in the suprachiasmatic nucleus of the hypothalamus, which coordinates peripheral clocks in organs throughout the body. Although circadian clocks control the rhythmic expression of a large number of genes involved in metabolism and other aspects of circadian physiology, the consequences of genetic disruption of circadiancontrolled pathways remain poorly defined. Here we report that the targeted disruption of Nocturnin (Ccrn4l) in mice, a gene that encodes a circadian deadenylase, confers resistance to dietinduced obesity. Mice lacking Nocturnin remain lean on high-fat diets, with lower body weight and reduced visceral fat. However, unlike lean lipodystrophic mouse models, these mice do not have fatty livers and do not exhibit increased activity or reduced food intake. Gene expression data suggest that Nocturnin knockout mice have deficits in lipid metabolism or uptake, in addition to changes in glucose and insulin sensitivity. Our data support a pivotal role for Nocturnin downstream of the circadian clockwork in the posttranscriptional regulation of genes necessary for nutrient uptake, metabolism, and storage.C ircadian clocks are present in most tissues of the body, where they control the expression of 5-10% of the tissue-specific mRNAs through both transcriptional and posttranscriptional regulation (1, 2). The widespread importance of circadian clock regulation is evident in that generalized disruption of normal clock function results in tumor formation, sleep disorders, and metabolic problems (reviewed in refs. 3 and 4). For example, mutations in the central clock genes Clock or Bmal1 result in metabolic changes found in obesity and the metabolic syndrome (5-8), and numerous genes involved in fatty acid, cholesterol, and glucose metabolism in liver are regulated in circadian or diurnal patterns (9-15), indicating that the clock plays a broad role in regulating metabolism. Nonetheless, the large number of genes, metabolic pathways, and cell/tissue types that are under general circadian control impose a major challenge in understanding the molecular details. Further advances in this area require refined understanding of the specific circadian output pathways by which the clocks regulate physiology.For cycling mRNAs to closely reflect daily rhythmic transcriptional drive, their half-lives must be relatively short. There are several examples of rhythmic posttranscriptional regulation in which the mRNA half-life or adenylation state changes over the course of the day (16-19), but very little is known about the mechanisms responsible. A likely contributor is Nocturnin (Ccrn4l, Noc), which has been implicated in the posttranscriptional regulation of mRNA stability and/or translatability by the circadian clock (20). Noc is expressed rhythmically in many tissues, with particularly high-amplitude rhythms in liver where mRNA levels are increased 100-fold in early night (21). Noc is at a pivotal position to play a role in shaping the rhythmic pattern of gene ...

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“…( Wolfrum et al 2001), and L-FABP dysfunction suppresses the PPARα-regulated pathway, particularly under a high-fat diet feeding condition (Newberry et al 2006). In the current study, the induction of the L-FABP gene was observed in the PUFA (+) mice at both 2 and 5 weeks, but not in the PUFA (−) groups at either time point.…”

Section: Discussionmentioning

confidence: 99%

Decreased Fatty Acid <i>β</i>-Oxidation Is the Main Cause of Fatty Liver Induced by Polyunsaturated Fatty Acid Deficiency in Mice

Nakajima

Yang

et al. 2017

Tohoku J. Exp. Med.

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Insufficient intake of polyunsaturated fatty acids (PUFA) causes fatty liver. The mechanism responsible is primarily related to increased lipogenesis and decreased FA degradation based on rodent studies. However, these studies were limited by the fact that the typical PUFA-deficient diets contained insufficient amounts of long-chain FA, the PUFA-containing diets were primarily composed of n-3 PUFA-enriched oil, and the intake of PUFA was excessive compared with the physiological requirement. To address these issues, mice were fed a PUFA-deficient diet containing long-chain FA at a standard fed level and then were orally fed a n-3/n-6-balanced PUFA-containing oil [PUFA (+)] or a PUFA-deficient oil [PUFA (−)] at physiological relevant levels (0.1 mL/mouse/2d). We compared these groups and examined whether fatty liver in PUFA deficiency was attributable to both the effects of increased lipogenesis and decreased FA catabolism. Compared with the PUFA (+) group, the PUFA (−) group showed increases in liver triglyceride and serum FA content. Hepatic gene expression of several mitochondrial β-oxidation enzymes, the serum 3-hydroxybutyrate level, and DNA-binding ability of peroxisome proliferator-activated receptor α (PPARα) were increased in the PUFA (+) group, whereas these adaptive responses were significantly attenuated in the PUFA (−) group. The hepatic expression of typical lipogenesis genes did not differ between the groups. Therefore, fatty liver in PUFA deficiency is attributable to suppression of the FA-degrading system probably from decreased PPARα adaptive responsiveness, and PUFA may be an essential factor for PPARα functioning. This finding is helpful for managing clinical situations having a risk of PUFA deficiency.

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Protection against Western diet–induced obesity and hepatic steatosis in liver fatty acid–binding protein knockout mice

Cited by 179 publications

References 47 publications

Liver Fatty Acid-binding Protein Initiates Budding of Pre-chylomicron Transport Vesicles from Intestinal Endoplasmic Reticulum

Liver Fatty Acid-binding Protein Initiates Budding of Pre-chylomicron Transport Vesicles from Intestinal Endoplasmic Reticulum

Loss of Nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity

Decreased Fatty Acid <i>β</i>-Oxidation Is the Main Cause of Fatty Liver Induced by Polyunsaturated Fatty Acid Deficiency in Mice

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