Fatty acid transport: the roads taken

Schaffer, Jean E.

doi:10.1152/ajpendo.00462.2001

Cited by 151 publications

(115 citation statements)

References 76 publications

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“…2). (Intracellular fatty acid binding proteins and acyl-CoA synthase are, of course, also involved in this process, as also are the putative fatty acid transporters [29]). Thus, the pathway of fatty acid uptake, or 'fatty acid trapping' [30], plays an important part in regulating NEFA delivery from adipose tissue in the postprandial state.…”

Section: Adipose Tissue and The Buffering Of Lipid Fluxmentioning

confidence: 99%

Adipose tissue as a buffer for daily lipid flux

2002

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Section: Adipose Tissue and The Buffering Of Lipid Fluxmentioning

confidence: 99%

Adipose tissue as a buffer for daily lipid flux

2002

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“…Levels of stearoyl-CoA desaturase 1 (SCD1) (27), long-chain fatty acid elongase (28), fatty acid transporter (CD36) (29), and the lipidresponsive nuclear hormone receptor peroxisome proliferatoractivated receptor ␥ (PPAR␥) (30) are all significantly decreased in PASK Ϫ/Ϫ liver (Fig. 4D).…”

Section: Pask ؊/؊ Mice Exhibit Increased Whole-body Energy Expenditurmentioning

confidence: 99%

PAS kinase is required for normal cellular energy balance

Hao¹,

Cardon²,

Swiatek³

et al. 2007

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

156

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The metabolic syndrome, a complex set of phenotypes typically associated with obesity and diabetes, is an increasing threat to global public health. Fundamentally, the metabolic syndrome is caused by a failure to properly sense and respond to cellular metabolic cues. We studied the role of the cellular metabolic sensor PAS kinase (PASK) in the pathogenesis of metabolic disease by using PASK ؊/؊ mice. We identified tissue-specific metabolic phenotypes caused by PASK deletion consistent with its role as a metabolic sensor. Specifically, PASK ؊/؊ mice exhibited impaired glucose-stimulated insulin secretion in pancreatic ␤-cells, altered triglyceride storage in liver, and increased metabolic rate in skeletal muscle. Further, PASK deletion caused nearly complete protection from the deleterious effects of a high-fat diet including obesity and insulin resistance. We also demonstrate that these cellular effects, increased rate of oxidative metabolism and ATP production, occur in cultured cells. We therefore hypothesize that PASK acts in a cell-autonomous manner to maintain cellular energy homeostasis and is a potential therapeutic target for metabolic disease.metabolism ͉ PAS domain ͉ nutrient sensing ͉ obesity B ecause of changes in diet and lifestyle, the incidence of obesity and type 2 diabetes is increasing dramatically worldwide. Type 2 diabetes arises when pancreatic ␤-cells fail to secrete sufficient insulin to compensate for peripheral insulin resistance, a condition severely aggravated by obesity (1, 2). Type 2 diabetes is now widely viewed as a manifestation of a broader underlying metabolic disorder called the metabolic syndrome, which is characterized by hyperglycemia, hyperinsulinemia, dyslipidemia, hypertension, visceral obesity, and cardiovascular disease (3). The World Health Organization estimates that the current decade will witness a 46% increase in diabetes incidence worldwide (from 151 million to 221 million), with the vast majority of this increase being due to metabolic syndrome-related type 2 diabetes (4).Cellular energy and nutrient sensors determine how cells respond to excessive nutrients, and aberrant nutrient and energy sensing is a contributing factor to metabolic syndrome development (5, 6). AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are two well studied and evolutionarily conserved cellular energy and nutrient sensors. AMPK is activated in response to intracellular ATP depletion and acts to switch the cellular metabolic program from ATP consumption to ATP production (7). In contrast to AMPK, mTOR is activated by sufficient cellular energy or nutrients, particularly amino acids (8). Activation of mTOR stimulates cell growth by increasing protein synthesis through phosphorylation of ribosomal S6 kinase (S6K) and eIF4E-binding protein (9). Decreased AMPK activity and elevated mTOR activity have been linked with obesity, diabetes, and cancer (10-12).Like AMPK and mTOR, PAS kinase (PASK) is a nutrientresponsive protein kinase conserved from yeast to humans. Th...

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“…Although cells can synthesize a subset of the fatty acids they require, efficient uptake of extracellular fatty acids is an important cellular function and is thought to be mediated in part by FATPs (17). Expression of FATPs in transfected cells increases the rate of uptake of long-chain fatty acids (18).…”

Section: Fatp4mentioning

confidence: 99%

Cloning of wrinkle-free, a previously uncharacterized mouse mutation, reveals crucial roles for fatty acid transport protein 4 in skin and hair development

Moulson

Martin

Lugus

et al. 2003

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

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111

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Wrinkle-free (wrfr) is a previously uncharacterized, spontaneous, autosomal recessive mouse mutation resulting in very tight, thick skin. wrfr mutant mice exhibit severe breathing difficulties secondary to their tight skin and die shortly after birth. This phenotype is strikingly similar to a very rare human genetic disorder, restrictive dermopathy. wrfr mutant mice display a defective skin barrier, which is normally imparted by the cornified envelope, a composite of protein and lipid that prevents loss of water from within and entry of potentially harmful substances from without. In addition, hair growth from grafted wrfr skin is impaired. Positional cloning of the wrfr mutation revealed a retrotransposon insertion into a coding exon of Slc27a4, the gene encoding fatty acid transport protein (FATP)4. FATP4 is the primary intestinal FATP and is thought to play a major role in dietary fatty acid uptake; it therefore is viewed as a target to prevent or reverse obesity. However, its function in vivo had not been determined. Our results demonstrate an unexpected yet critical role for FATP4 in skin and hair development and suggest Slc27a4 to be a candidate gene for restrictive dermopathy.T he skin of mammals is composed of a dermis and an epidermis separated by a basement membrane. The epidermis is stratified, consisting of basal keratinocyte, spinous͞ prickle, granular, and squamous͞cornified layers. Keratinocytes move upward from the basement membrane and progress through a scheduled program of differentiation, with cell death marking their final differentiation step. During this differentiation program, keratinocytes flatten and accumulate lipids that are discharged into the intercellular space (1). In the stratum corneum the lipids are crosslinked with a number of proteins including loricrin and involucrin to form the cornified envelope (2). The insoluble cornified envelope is a composite of protein and lipid that serves as a barrier to loss of water from within and to entry of potentially harmful substances from without. Without such a barrier, life on land could not exist (3).We discovered a spontaneous, autosomal recessive mutation in our mouse colony causing extremely tight, thick skin. We named the mutation wrinkle-free (wrfr). The wrfr phenotype is similar to a rare human disease called restrictive dermopathy (4, 5). Newborn wrfr Ϫ͞Ϫ mice have difficulty breathing because of the tight skin, do not suckle, exhibit a defective skin barrier, and die several hours after birth. There are also defects in hair follicle morphogenesis and hair growth. Because of the presumed fundamental importance of the mutated gene to skin development and its potential relevance to human disease, we sought to identify the affected gene. Here we present a characterization of the wrfr phenotype and the positional cloning of the wrfr mutation. Materials and MethodsMicrosatellite Marker Analysis. Genomic DNA was prepared from tissues by standard proteinase K digestion, phenol͞chloroform extraction, and ethanol precipitation (6) or by ...

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Fatty acid transport: the roads taken

Cited by 151 publications

References 76 publications

Adipose tissue as a buffer for daily lipid flux

Adipose tissue as a buffer for daily lipid flux

PAS kinase is required for normal cellular energy balance

Cloning of wrinkle-free, a previously uncharacterized mouse mutation, reveals crucial roles for fatty acid transport protein 4 in skin and hair development

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