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PubMed1996

A speculative model of affective illness cyclicity based on patterns of drug tolerance observed in amygdala-kindled seizures.

In this article, we discuss molecular mechanisms involved in the evolution of amygdala kindling and the episodic loss of response to pharmacological treatments during tolerance development. These phenomena allow us to consider how similar principles (in different neurochemical systems) could account for illness progression, cyclicity, and drug tolerance in affective disorders. We describe the phenomenon of amygdala-kindled seizures episodically breaking through effective daily pharmacotherapy with carbamazepine and valproate, suggesting that these observations could reflect the balance of pathological vs compensatory illness-induced changes in gene expression. Under certain circumstances, amygdala-kindled animals that were initially drug responsive can develop highly individualized patterns of seizure breakthroughs progressing toward a complete loss of drug efficacy. This initial drug efficacy may reflect the combination of drug-related exogenous neurochemical mechanisms and illness-induced endogenous compensatory mechanisms. However, we postulate that when seizures are inhibited, the endogenous illness-induced adaptations dissipate (the "time-off seizure" effect), leading to the re-emergence of seizures, a re-induction of a new, but diminished, set of endogenous compensatory mechanisms, and a temporary period of renewed drug efficacy. As this pattern repeats, an intermittent or cyclic response to the anticonvulsant treatment emerges, leading toward complete drug tolerance. We also postulate that the cyclic pattern accelerates over time because of both the failure of robust illness-induced endogenous adaptations to emerge and the progression in pathophysiological mechanisms (mediated by long-lasting changes in gene expression and their downstream consequences) as a result of repeated occurrences of seizures. In this seizure model, this pattern can be inhibited and drug responsivity can be temporarily reinstated by several manipulations, including lowering illness drive (decreasing the stimulation current), increasing drug dosage, switching to a new drug that does not show crosstolerance to the original medication, or temporarily discontinuing treatment, allowing the illness to re-emerge in an unmedicated animal. Each of these variables is discussed in relation to the potential relevance to the emergence, progression, and suppression of individual patterns of episodic cyclicity in the recurrent affective disorders. A variety of clinical studies are outlined that specifically test the hypotheses derived from this formulation. Data from animal studies suggest that illness cyclicity can develop from the relative ratio between primary pathological processes and secondary endogenous adaptations (assisted by exogenous medications). If this proposition is verified, it further suggests that illness cyclicity is inherent to the neurobiological processes of episode emergence and amelioration, and one does not need to postulate a separate defect in the biological clock. The formulation predicts that early and aggressive long-term interventions may be optimal in order to prevent illness emergence and progression and its associated accumulating neurobiological vulnerability factors.

Affect↗
PubMed1995

[Asymmetry of the human facial nerve].

Measurements of the right and left facial skull were carried out in 6 different series of skulls: two europeoid, Russian and Georgian; two mongoloid, Buryat and Eskimo; and two skulls of mixed origin, Khakass and Udmurt ones, in order to assess the bilateral asymmetry. The measurements included 18 signs characterizing the width, height, and length of the facial skull. Sums of all right-side and left-side signs were the integral parameters of the right and left halves of the facial skull. A compensatory type of asymmetry variations was revealed. All the components of the facial skull regarded individually demonstrate clear asymmetry, whereas the total summary size of both halves of the facial skull is similar. The cause of the symmetrical combination of whole parts in the presence of evident asymmetry of various elements of the facial skull is differently directed asymmetry of various extent. The results are discussed in the context of the evolution of human functions and the relevant transformation of the morphologic structure in the anthropogenesis.

Asian People↗
PubMedDate not supplied

Morphometric assessment of nucleolar activity in liver cells during the evolutive pathway of chronic hepatitis C to cirrhosis.

Using a computer-assisted image analysis system, we performed a morphometric study of silver-stained nucleoli of hepatocytes in liver biopsy specimens from hepatitis C virus-positive patients with chronic persistent hepatitis (3 cases), chronic active hepatitis (4 cases), and cirrhosis (4 cases). The number and the total area of nucleoli, the average area of each nucleolus and the nuclear area were determined for each of 100 hepatocytes per case. A continuing increase in the area of both nucleoli and nuclei paralleled a progressive decrease in the number of nucleoli during the evolution of chronic hepatitis C to liver cirrhosis. These findings would indicate that the hepatitis C virus-induced liver damage causes reactive changes in surviving hepatocytes resulting in an increased nucleolar biosynthetic activity rather than in an increment of cell proliferation rate. Therefore, the liver response to hepatitis C virus injury seems to be mainly based on a condition of cell "hypertrophy", whereas we previously showed that a process also of compensatory hyperplasia occurs in chronic hepatitis B, possibly resulting from a different pathogenesis of the viral damage.

Cell Nucleolus↗
PubMed1997

Genetic code synonym quotas and amino acid complexity: cutting the cost of proteins?

The synonym quotas within the genetic code for the 20 common amino acids are examined in relation to the ways in which these amino acids can be marshalled into different sets on the basis of shared physico-chemical properties. This reveals which shared properties are encouraged or discouraged during the course of protein evolution by the arrangement of the code. A dominant theme is that the synonym quotas are allocated in favour of small and chemically uncomplicated residues, and to the disadvantage of large and chemically prominent ones. From amongst the various measurements that can be considered to quantitatively express aspects of amino acid residue "size and complexity" (e.g. side chain volume, bulkness and formula weight), formula weight has the highest correlation with the synonym quota for each amino acid. However, the correlation is weak. A specially derived "size/complexity" scale for the amino acids based on their relative atomic composition improved the correlation only marginally. The existence of another weak correlation between the synonym quotas and the general amino acid composition of proteins prompted an investigation of the correlations between this composition and the previously considered amino acid properties. Again, the highest correlations are with amino acid formula weight and "size/complexity", but in this instance the correlations are high enough to be truly significant. It is suggested that the biased synonym quotas in the genetic code are intended to ensure that proteins as a whole maintain a certain amino acid composition, even to the extent that the quotas include compensatory biases to counter opposing influences upon this composition caused by the processes of natural selection for protein function. It is the need for these compensatory biases that prevents a simple correlation between the quotas and measures of amino acid complexity. The final outcome, in which amino acids are deployed in functional proteins in approximate proportion to their chemical complexity may serve both as a means of minimising the negative consequences of random genetic mutation (by reducing the chance appearance of the more "disruptive" types of side chain in proteins) and as a means of ensuring the most economic use of biosynthetic resources. According to this reasoning, the code is not a "frozen accident"; it is universally appropriate because it provides the best compromise that can be achieved between biosynthetic cost and biological return in respect of the rate of protein evolution.

Amino Acids↗
PubMed1996

Modifying the sequence of an immunoglobulin V-gene alters the resulting pattern of hypermutation.

Affinity maturation of antibodies requires localized hypermutation and antigen selection. Hypermutation is particularly active in certain regions (notably the CDRs of light and heavy chains) due to the local accumulation of hot spots. We have now analyzed the role of individual nucleotides in the origin of hot spots and show that mutability is largely defined by the nucleotide sequence. We compared the mutability profile of wild-type and modified kappa transgenes that contain silent mutations in the CDR1 segment. We found a new hot spot created at the third base of Ser-31 when its wild-type AGT codon was substituted by AGC. Two major hot spots associated with this AGC vanished when Ser-31 was encoded by the synonymous TCA. In addition to these, which were the most prominent changes, there were compensatory alterations in mutability of residues not directly related to the introduced silent mutations, so that the average hypermutation remained constant. Thus, mutations arising early in the immune response, even silent ones, could affect the mutability of critical residues and alter the pattern of affinity maturation. When analyzing hybridomas, we detected such alterations, but they seemed to better correlate with changes in average rather than local mutation rates. Overall, this paper shows how evolution could have optimized the mutability of individual residues to minimize deleterious mutations. Thus, the optimal strategy for affinity maturation may involve the incorporation of multiple point mutations before antigen selection of the relevant cells.

Animals↗
PubMed2000

Alphavirus RNA genome repair and evolution: molecular characterization of infectious sindbis virus isolates lacking a known conserved motif at the 3' end of the genome.

The 3' nontranslated region of the genomes of Sindbis virus (SIN) and other alphaviruses carries several repeat sequence elements (RSEs) as well as a 19-nucleotide (nt) conserved sequence element (3'CSE). The 3'CSE and the adjoining poly(A) tail of the SIN genome are thought to act as viral promoters for negative-sense RNA synthesis and genome replication. Eight different SIN isolates that carry altered 3'CSEs were studied in detail to evaluate the role of the 3'CSE in genome replication. The salient findings of this study as it applies to SIN infection of BHK cells are as follows: i) the classical 19-nt 3'CSE of the SIN genome is not essential for genome replication, long-term stability, or packaging; ii) compensatory amino acid or nucleotide changes within the SIN genomes are not required to counteract base changes in the 3' terminal motifs of the SIN genome; iii) the 5' 1-kb regions of all SIN genomes, regardless of the differences in 3' terminal motifs, do not undergo any base changes even after 18 passages; iv) although extensive addition of AU-rich motifs occurs in the SIN genomes carrying defective 3'CSE, these are not essential for genome viability or function; and v) the newly added AU-rich motifs are composed predominantly of RSEs. These findings are consistent with the idea that the 3' terminal AU-rich motifs of the SIN genomes do not bind directly to the viral polymerase and that cellular proteins with broad AU-rich binding specificity may mediate this interaction. In addition to the classical 3'CSE, other RNA motifs located elsewhere in the SIN genome must play a major role in template selection by the SIN RNA polymerase.

3' Untranslated Regions↗
PubMedDate not supplied

Achromatic parvocellular contrast gain in normal and color defective observers: Implications for the evolution of color vision.

The PC pathway conveys both chromatic and achromatic information, with PC neurons being more responsive to chromatic (L-M) than to achromatic (L+M) stimuli. In considering the evolution of color vision, it has been suggested that the dynamic range of chromatic PC-pathway processing is tuned to the chromatic content of the natural environment. Anomalous trichromats, with reduced separation of their L- and M-cone spectral sensitivities, have diminished chromatic input to PC-pathway cells. Dichromats, with absent L or M cones, should have no chromatic input to PC-pathway cells. Therefore, the PC-pathway dynamic range of color defectives should be released from any constraint imposed by the chromatic environment. Here we ask whether this results in compensatory enhancement of achromatic PC-pathway processing in color defectives. This study employed a psychophysical method designed to isolate PC-pathway processing using achromatic stimuli. In a pulsed-pedestal condition, a four-square stimulus array appeared within a uniform surround. During a trial, one of the test squares differed from the other three, and the observer's task was to choose the square that was different. A four-alternative, forced-choice method was used to determine thresholds as a function of the contrast of the four-square array to the surround. Seven color defective and four normal observers participated. Results showed no systematic differences between normals and color defectives. There was no enhancement of achromatic processing as compensation for reduced chromatic processing in the PC-pathway system in color defectives. From physiological recordings, PC-pathway achromatic contrast gains of dichromatic and trichromatic New World primates and trichromatic Old World macaques have also been shown to be similar to each other. Our study and the animal studies imply that PC-pathway contrast gain parameters were regulated by factors other than the environmental chromaticity gamut, and may have arisen in a nontrichromatic common ancestor to both Old and New World primates.

Animals↗
PubMed2001

Evolution of transcript structure and base composition of rDNA expansion segment D3 in ticks.

Four to thirty-two copies of the rDNA 28S gene expansion segment D3 and flanking H14 stem were sequenced in six species of ticks (Ixodes: Ixodidae: Acari). Sequence match among species varied from 66% to 97%. Sequence length averaged 130 bases in I. persulcatus across eight Eurasian sites and averaged 186 bases in five other species across 19 Eurasian and North American sites. The difference in length represents one or more deletions totalling about 60 bases that correspond to stems S3 or S4 of the folded transcript. The typical transcript conformation was observed as one possible low energy structure in the five species of longer D3. The structure entails a basal loop with four stem/loop structures, S1-S4 (moving 5' to 3') atop stem H14. A secondary structure lacking S4 but possessing all other putative standard features of the D3 transcript is possible with the shorter I. persulcatus sequences. Interspecific sequence differences occur at higher frequency in loops and bulges vs. complementary pairing regions of stems. Insertion/deletion events (indels) and base substitutions accounted equally for sequence differences. Indels are flanked by similar sequences, suggesting that they occur by slippage during replication. The D3 of Ixodes species is composed of a degenerate set of subrepeats. Thus, unequal exchange among subrepeats may have caused the reduction in length of the I. persulcatus D3. Compensatory base substitution and compensatory insertion/deletion events are indicated by the failure of mutations to affect secondary structure. Transversions accounted for 64% of sequence differences and were biased toward the gain of G and U and the loss of A and C. This bias could re-establish intramolecular base pairing when disrupted by insertions or deletions that shift one side of a stem relative to the other. The distribution of sequence differences, biased substitution, and conservation of transcript conformation in D3 suggest selective constraint.

Animals↗
PubMed2005

Human disease-associated mitochondrial mutations fixed in nonhuman primates.

A number of human disease-associated sequences have been reported in other species, such as rodents, but compensatory changes appear to prevent these deleterious mutations from being expressed. The aim of this work was to compare the mitochondrial DNA of multiple primates to ascertain whether mitochondrial disease-causing sequences in humans are fixed in nonhuman primates. Indeed, 46 sequences related to human pathology were identified in 1 or more of the 12 studied nonhuman primates, the majority of which were associated with late-onset diseases. Most of these sequences can be explained by the presence of secondary compensatory changes that render these mutations phenotypically inert. Nonetheless, and since humans not only are the longest-lived primate but feature the largest brain, one hypothesis is that a gradual optimization of the human mitochondrion occurred in the hominid lineage driven by the need to optimize the aerobic energy metabolism to delay neurodegeneration. Therefore, it is also proposed that some of these disease-associated sequences in nonhuman primates may be linked to the evolution of human longevity and intelligence, indicating a general pattern of selection on longevity in the course of evolution of the human mitochondrion.

Animals↗
PubMed2005

Evolutionary approaches to understanding sleep.

A major controversy over REM sleep's role in memory processing may owe to inadequate allowances for the highly conservative nature of evolutionary adaptations. The controversy hinges on whether NREM sleep, alone, retains primitive memory processing capabilities. The selective pressure for primitive sleep, is thought to have been the need to obviate conflicts between enormous neural processing requirements of complex visual analysis and split-second control of movements, on the one hand, and memory processing, on the other. The most efficient memory processing during mammalian and avian sleep appears to be a two-step process: synapses in individual component circuits of events are reinforced primarily by slow brain waves during NREM sleep, with the reinforced components temporally bound by fast waves, and manifested as dreams, during REM sleep. This dual action could account for partitioning of sleep periods into multiple NREM-REM cycles. It is proposed that in the absence of REM sleep, all needed memory processing can be accomplished by NREM sleep, alone, though less efficiently. Many symptoms of fatal familial insomnia are attributed to subnormal nightly reinforcement of brain circuitry because of almost total loss of sleep, and compensatory responses thereto during waking. During this disorder, sensory circuitry seemingly is spared by virtue of its supernormal reinforcement during almost continuous waking. Contrariwise, sparing of an adult's 'higher faculties' in encephalitis lethargica appears to owe to supernormal circuit reinforcement during almost continuous sleep.

Awareness↗
PubMed1978

Intracranial pressure reserve testing. Initial clinical observations.

Sequential subdural injections of fluid through an intracranial pressure (ICP) monitoring cup catheter have been employed to measure "ICP reserve" in a series of 136 determinations in 30 patients over a total of 155 days of recordings. This dynamic method of quantitating the brain's ability to adapt to increased intracranial volume tests the brain's compensatory mechanisms over a five-minute time span. The test, incorporating several safety features, has been found to be reliable, safe, and well tolerated. A series of observations have been made using this test in patients with subdural drains and in response to fluid, mannitol, and dexamethasone therapy. Deteriorating ICP reserve gave early warning of the need for reoperation for postoperative hematoma, massive brain swelling, or cystic reaccumulation. Intracranial pressure reserve testing also quantitated the evolution of postoperative brain edema. Changes in ICP reserve could be detected as much as 48 hours before changes in baseline ICP and as much as 72 hours before clinical deterioration was evident.

Brain↗
PubMed2000

Pervasive compensatory adaptation in Escherichia coli.

To investigate compensatory adaptation (CA), we used genotypes of Escherichia coli which were identical except for one or two deleterious mutations. We compared CA for (i) deleterious mutations with large versus small effects, (ii) genotypes carrying one versus two mutations, and (iii) pairs of deleterious mutations which interact in a multiplicative versus synergistic fashion. In all, we studied 14 different genotypes, plus a control strain which was not mutated. Most genotypes showed CA during 200 generations of experimental evolution, where we define CA as a fitness increase which is disproportionately large relative to that in evolving control lines, coupled with retention of the original deleterious mutation(s). We observed greater CA for mutations of large effect than for those of small effect, which can be explained by the greater benefit to recovery in severely handicapped genotypes given the dynamics of selection. The rates of CA were similar for double and single mutants whose initial fitnesses were approximately equal. CA was faster for synergistic than for multiplicative pairs, presumably because the marginal gain which results from CA for one of the component mutations is greater in that case. The most surprising result in our view, is that compensation should be so readily achieved in an organism which is haploid and has little genetic redundancy This finding suggests a degree of versatility in the E. coil genome which demands further study from both genetic and physiological perspectives.

Adaptation, Physiological↗
PubMed1997

Microhabitat use, trophic patterns, and the evolution of brain structure in African cichlids.

The species assemblages of cichlids in the three largest African Great Lakes are among the richest concentrations of vertebrate species on earth. The faunas are broadly similar in terms of trophic diversity, species richness, rates of endemism, and taxonomic composition, yet they are historically independent of each other. Hence, they offer a true and unique evolutionary experiment to test hypotheses concerning the mutual dependencies of ecology and brain morphology. We examined the brains of 189 species of cichlids from the three large lakes: Victoria, Tanganyika, and Malawi. A first paper demonstrated that patterns of evolutionary change in cichlid brain morphology are similar across taxonomic boundaries as well as across the three lakes [van Staaden et al., 1995 ZACS 98: 165-178]. Here we report a close relationship between the relative sizes of various brain structures and variables related to the utilization of habitat and prey. Causality is difficult to assign in this context, nonetheless, prey size and agility, turbidity levels, depth, and substrate complexity are all highly predictive of variation in brain structure. Areas associated with primary sensory functions such as vision and taste relate significantly to differences in feeding habits. Turbidity and depth are closely associated with differences in eye size, and large eyes are associated with species that pick plankton from the water column. Piscivorous taxa and others that utilize motile prey are characterized by a well developed optic tectum and a large cerebellum compared to species that prey on molluscs or plants. Structures relating to taste are well developed in species feeding on benthos over muddy or sandy substrates. The data militated against the existence of compensatory changes in brain structure. Thus enhanced development of a particular function is generally not accompanied by a parallel reduction of structures related to other modalities. Although genetic and environmental influences during ontogeny of the brain cannot be isolated, this study provides a rich source of hypotheses concerning the way the nervous system functions under various environmental conditions and how it has responded to natural selection.

Africa↗
PubMed2003

Compensatory mutations cause excess of antagonistic epistasis in RNA secondary structure folding.

BACKGROUND: The rate at which fitness declines as an organism's genome accumulates random mutations is an important variable in several evolutionary theories. At an intuitive level, it might seem natural that random mutations should tend to interact synergistically, such that the rate of mean fitness decline accelerates as the number of random mutations is increased. However, in a number of recent studies, a prevalence of antagonistic epistasis (the tendency of multiple mutations to have a mitigating rather than reinforcing effect) has been observed. RESULTS: We studied in silico the net amount and form of epistatic interactions in RNA secondary structure folding by measuring the fraction of neutral mutants as a function of mutational distance d. We found a clear prevalence of antagonistic epistasis in RNA secondary structure folding. By relating the fraction of neutral mutants at distance d to the average neutrality at distance d, we showed that this prevalence derives from the existence of many compensatory mutations at larger mutational distances. CONCLUSIONS: Our findings imply that the average direction of epistasis in simple fitness landscapes is directly related to the density with which fitness peaks are distributed in these landscapes.

Animals↗
PubMedDate not supplied

[The nerve centers of the emotions].

The participation and the role of the brain formations in the genesis of emotional reactions of higher animals and man are discussed according to E.A. Asratian's concept of the nervous centre as a complex of brain structures, situated in different areas of the central nervous system, comprising the total morpho-functional unity and realizing a definite specific function. The data are given testifying that the frontal and temporal areas of the neocortex, hippocampus, amygdala and hypothalamus are correspondingly connected with reflecting-estimating, compensatory, transferring and reinforcing functions of emotions. The reinforcing function is phylogenetically the most ancient. It is connected with solution of the universal behavioural task of maximization-minimization of the appeared emotion, striving for "to" or "from". Replacing and transferring functions have been formed later, while reflecting-estimating one is the most young. It namely provides the wealth and diversity of emotions, based on complicated vital, social and cognitive needs. Such succession coincides with the evolution of the corresponding brain formations, with their phylogenetic age.

Affect↗
PubMed1987

[Original adaptive characters of intestinal Digenea of Sarpa salpa (Teleostei, Sparidae) and their interpretation in terms of evolution].

In the family Sparidae, the genus Sarpa is distinguished by a few characteristics: monospecificity, vegetarian diet and wide geographical distribution. The helminth fauna of Sarpa salpa is also very original. Indeed, the digenean parasites of this Teleostean fish are essentially classified into two families restricted to this fish. In the present paper, the author redescribes Mesometra orbicularis, M. brachycoelia, Centroderma spinosissima, Elstia stossichianum, Wardula capitellata (family Mesometridae) together with Robphildollfusium fractum (family Robphildollfusidae). Various original and yet unknown features are pointed out. Among these unusual structures, several correspond to adaptive characteristics favouring the settlement of the Digenean on the peculiar digestive gut wall of this herbivorous fish. Indeed, the intestinal mucous membrane of Sarpa salpa exhibits very few villi giving it an unusual smooth aspect. Therefore, the Mesometridae which always have just a single sucker (monostomatous) have selected a new kind of compensatory adhesive structure. Sometimes, the anterior end of the body becomes a sucker due to the particular distribution of the muscle strings; in other examples, the whole body becomes a sucker and its edges become considerably thinner to improve the tightness of the adhesive system. Other original anatomical features have been selected to allow survival in a medium rich in plant detritus. So, in the oral sucker crests ornemented by numerous sclerous denticles seem to act as a microfilter for the intestinal chyme in which plant fibres predominate. The original pharynx seems to act as a suction-force pump. The excretory system, which is of a reticular type, penetrates the whole parenchyma and this could be a response to huge intestinal fermentations. The Digenea of Sarpa salpa are not interpreted by the author as true parasites but as endocommensal symbionts. These inquiline species are not immunogenic, or at least only slightly so, since they do not feed upon the host itself but upon its intestinal chyme. In most cases this results in a high parasite density (post larvae and adults) together with a cohabitation of the various species along the various intestinal segments. Coexistence of several species, systematically very close, evidently raises the question of their reproductive isolation. The author proposes an answer founded upon data of allopatric speciation.

Adaptation, Physiological↗
PubMed2003

Complete alanine scanning of intersubunit interfaces in a foot-and-mouth disease virus capsid reveals critical contributions of many side chains to particle stability and viral function.

Spherical virus capsids are large, multimeric protein shells whose assembly and stability depend on the establishment of multiple non-covalent interactions between many polypeptide subunits. In a foot-and-mouth disease virus capsid, 42 amino acid side chains per protomer are involved in noncovalent interactions between pentameric subunits that function as assembly/disassembly intermediates. We have individually truncated to alanine these 42 side chains and assessed their relevance for completion of the virus life cycle and capsid stability. Most mutations provoked a drastic reduction in virus yields. Nearly all of these critical mutations led to virions whose thermal inactivation rates differed from that of the parent virus, and many affected also early steps in the viral cycle. Rapid selection of genotypic revertants or variants with forward or compensatory mutations that restored viability was occasionally detected. The results with this model virus indicate the following. (i). Most of the residues at the interfaces between capsid subunits are critically important for viral function, in part but not exclusively because of their involvement in intersubunit recognition. Each hydrogen bond and salt bridge buried at the subunit interfaces may be important for capsid stability. (ii). New mutations able to restore viability may arise frequently at the subunit interfaces during virus evolution. (iii). A few interfacial side chains are functionally tolerant to truncation and may provide adequate mutation sites for the engineering of a thermostable capsid, potentially useful as an improved vaccine.

Alanine↗
PubMed2004

Fatty acid-binding proteins--insights from genetic manipulations.

Fatty acid-binding proteins (FABPs) belong to the conserved multigene family of the intracellular lipid-binding proteins (iLBPs). These proteins are ubiquitously expressed in vertebrate tissues, with distinct expression patterns for the individual FABPs. Various functions have been proposed for these proteins, including the promotion of cellular uptake and transport of fatty acids, the targeting of fatty acids to specific metabolic pathways, and the participation in the regulation of gene expression and cell growth. Novel genetic tools that have become available in recent years, such as transgenic cell lines, animals, and knock-out mice, have provided the opportunity to test these concepts in physiological settings. Such studies have helped to define essential cellular functions of individual FABP-types or of combinations of several different FABPs. The deletion of particular FABP genes, however, has not led to gross phenotypical changes, most likely because of compensatory overexpression of other members of the iLBP gene family, or even of unrelated fatty acid transport proteins. This review summarizes the properties of the various FABPs expressed in mammalian tissues, and discusses the transgenic and ablation studies carried out to date in a functional context.

Animals↗