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Acsl5 KO display normal weight gain in response to high fat diet. Acsl5 WT and KO mice, females or males, (5 per group), were fed a Western type diet for 13 weeks and body weights were recorded. No significant differences are observed between Acsl5 KO and WT animals.
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Background
The absorption of dietary long chain fatty acids (LCFA) largely occurs in the jejunum. LCFA are activated via conjugation with Coenzyme A (CoA), a reaction catalyzed by Acyl-CoA synthetases (ACS). Acyl-CoA sythesis is critical for dietary LCFA absorption; yet, the jejunal ACS enzymes that catalyze the reaction are largely unknown.
Findi...
Citations
... ACSL catalyzes the first step of TG resynthesis. ACSL5 and ACSL3 are the main synthetases in the intestine and ACSL5 contributes 60%-80% of the total activity of intestinal ACSL activity (Meller N et al., 2013). ACSL5 transports FAs for lipid biosynthesis. ...
... TG absorption, lower fat mass, lower blood TG and glucose levels, and increased insulin sensitivity without acute postnatal complications (Bowman et al., 2016). Meanwhile, dietary LCFA absorption and body weight gain remained unaffected in Acsl5 −/− mice, possibly due to the residual ACSL activity that can maintain normal LCFA absorption (Meller N et al., 2013). However, Acsl5 deficiency may impair intestinal epithelium. ...
The incidence of obesity and associated metabolic diseases is increasing globally, adversely affecting human health. Dietary fats, especially triglycerides, are an important source of energy for the body, and the intestine absorbs lipids through a series of orderly and complex steps. A long-term high-fat diet leads to intestinal dysfunction, inducing obesity and metabolic disorders. Therefore, regulating dietary triglycerides absorption is a promising therapeutic strategy. In this review, we will discuss diverse aspects of the dietary triglycerides hydrolysis, fatty acid uptake, triglycerides resynthesis, chylomicron assembly, trafficking, and secretion processes in intestinal epithelial cells, as well as potential targets in this process that may influence dietary fat-induced obesity and metabolic diseases. We also mention the possible shortcomings and deficiencies in modulating dietary lipid absorption targets to provide a better understanding of their administrability as drugs in obesity and related metabolic disorders.
... Bowman et al. [16] found that inactivation of Acsl5 in the whole body resulted in approximately 50% reduction in hepatic ACSL activity. However, Meller et al. [35] found no significant decrease in ACSL activity in homogenates of primary hepatocytes from Acsl5 knockout mice compared with wildtype littermates. The reasons for the observed differences are not clear. ...
... These findings suggested that ACSL5 may be essential in intestinal fat absorption. However, in another study exploring the effects of Acsl5 knockout on intestinal fatty acid absorption, mice were gavaged with 50 ul olive oil, supplemented with 3 H labelled oleic acid, and radiotracer levels were measured in plasma 90 min after gavage [35]. No difference in the accumulation of plasma radiotracer between Acsl5 knockout mice and wild-type was observed, suggesting that Acsl5 knockout did not affect intestinal fatty acid absorption [35]. ...
... However, in another study exploring the effects of Acsl5 knockout on intestinal fatty acid absorption, mice were gavaged with 50 ul olive oil, supplemented with 3 H labelled oleic acid, and radiotracer levels were measured in plasma 90 min after gavage [35]. No difference in the accumulation of plasma radiotracer between Acsl5 knockout mice and wild-type was observed, suggesting that Acsl5 knockout did not affect intestinal fatty acid absorption [35]. It is possible that gavage with 50 ul olive oil only forms fewer lipid droplets, and thus the effects of Acsl5 knockout on plasma triglycerides are diminished. ...
Free fatty acids (FFAs) are essential energy sources for most body tissues. A fatty acid must be converted to fatty acyl-CoA to oxidize or be incorporated into new lipids. Acyl-CoA synthetase long-chain family member 5 (ACSL5) is localized in the endoplasmic reticulum and mitochondrial outer membrane, where it catalyzes the formation of fatty acyl-CoAs from long-chain fatty acids (C16–C20). Fatty acyl-CoAs are then used in lipid synthesis or β-oxidation mediated pathways. ACSL5 plays a pleiotropic role in lipid metabolism depending on substrate preferences, subcellular localization and tissue specificity. Here, we review the role of ACSL5 in fatty acid metabolism in multiple metabolic tissues, including the liver, small intestine, adipose tissue, and skeletal muscle. Given the increasing number of studies suggesting the role of ACSL5 in glucose and lipid metabolism, we also summarized the effects of ACSL5 on circulating lipids and insulin resistance.
... Moreover, previous research suggests the dysregulated expression of both ACSL3 and ACSL4 is linked to several diseases, especially cancer (Tang et al., 2018). ACSL5 has the highest expression in intestinal mucosa relative to other tissues (Meller et al., 2013). The splice variants in ACSL5 is associated with several types of cancer (Perez-Nunez et al., 2019), and a deletion of ACSL5 can lead to intestinal lipid malabsorption (O'Brien et al., 2020). ...
Goat milk is rich in fat and protein, thus, has high nutritional values and benefits human health. However, goaty flavour is a major concern that interferes with consumer acceptability of goat milk and the 4-alkyl-branched-chain fatty acids (vBCFAs) are the major substances relevant to the goaty flavour in goat milk. Previous research reported that the acyl-coenzyme A synthetases (ACSs) play a key role in the activation of fatty acids, which is a prerequisite for fatty acids entering anabolic and catabolic processes and highly involved in the regulation of vBCFAs metabolism. Although ACS genes have been identified in humans and mice, they have not been systematically characterized in goats. In this research, we performed genome-wide characterization of the ACS genes in goats, identifying that a total of 25 ACS genes (without ACSM2A) were obtained in the Capra hircus and each ACS protein contained the conserved AMP-binding domain. Phylogenetic analysis showed that out of the 25 genes, 21 belonged to the ACSS, ACSM, ACSL, ACSVL, and ACSBG subfamilies. However, AACS, AASDH, ACSF, and ACSF3 genes were not classified in the common evolutionary branch and belonged to the ACS superfamily. The genes in the same clade had similar conserved structures, motifs and protein domains. The expression analysis showed that the majority of ACS genes were expressed in multi tissues. The comparative analysis of expression patterns in non-lactation and lactation mammary glands of goat, sheep and cow indicated that ACSS2 and ACSF3 genes may participate in the formation mechanisms of goaty flavour in goat milk. In conclusion, current research provides important genomic resources and expression information for ACSs in goats, which will support further research on investigating the formation mechanisms of the goaty flavour in goat milk.
... T. ovatus and zebrafish acsl5 is mainly distributed in the brain, spleen, kidney and liver, which has similar results to zebrafish. In contrast, mammal Acsl5 is mainly expressed in the intestine, with less expression in the liver and kidney [28,29]. Additionally, mammalian Acsl6 is strictly expressed in the brain and testis [2,14], while a widely widespread distribution pattern of the acsl6 gene was found in the analyzed tissues of T. ovatus, zebrafish and grass carp [2,16]. ...
Long chain acyl-coA synthase (acsl) family genes activate the conversion of long chain fatty acids into acyl-coA to regulate fatty acid metabolism. However, the evolutionary characteristics, tissue expression and nutritional regulation of the acsl gene family are poorly understood in fish. The present study investigated the molecular characterization, tissue expression and nutritional regulation of the acsl gene family in golden pompano (Trachinotus ovatus). The results showed that the coding regions of acsl1, acsl3, acsl4, acsl5 and acsl6 cDNA were 2091 bp, 2142 bp, 2136 bp, 1977 bp and 2007 bp, encoding 697, 714, 712, 659 and 669 amino acids, respectively. Five acsl isoforms divided into two branches, namely, acsl1, acsl5 and acsl6, as well as acsl3 and acsl4. The tissue expression distribution of acsl genes showed that acsl1 and acsl3 are widely expressed in the detected tissues, while acsl4, acsl5 and acsl6 are mainly expressed in the brain. Compared to the fish fed with lard oil diets, the fish fed with soybean oil exhibited high muscular C18 PUFA contents and acsl1 and acsl3 mRNA levels, as well as low muscular SFA contents and acsl4 mRNA levels. High muscular n-3 LC-PUFA contents, and acsl3, acsl4 and acsl6 mRNA levels were observed in the fish fed with fish oil diets compared with those of fish fed with lard oil or soybean oil diets. High n-3 LC-PUFA levels and DHA contents, as well as the acsl3, acsl4 and acsl6 mRNA levels were exhibited in the muscle of fish fed diets with high dietary n-3 LC-PUFA levels. Additionally, the muscular acsl3, acsl4 and acsl6 mRNA expression levels, n-3 LC-PUFA and DHA levels were significantly up-regulated by the increase of dietary DHA proportions. Collectively, the positive relationship among dietary fatty acids, muscular fatty acids and acsl mRNA, indicated that T. ovatus Acsl1 and Acsl3 are beneficial for the C18 PUFA enrichment, and Acsl3, Acsl4 and Acsl6 are for n-3 LC-PUFA and DHA enrichment. The acquisition of fish Acsl potential function in the present study will play the foundation for ameliorating the fatty acids nutrition in farmed fish products.
... Similar to Fatp4, LCFA ACS-5 (or Acsl5 in the mouse) is also highly expressed in mouse jejunum [126]. While Acsl5 KO mice fed high-fat diet (HFD) displayed a decrease in ACS activity, they did not show any changes in dietary FA absorption and body-weight gain. ...
Fatty acid (FA) metabolism is a series of processes that provide structural substances, signalling molecules and energy. Ample evidence has shown that FA uptake is mediated by plasma membrane transporters including FA transport proteins (FATPs), caveolin-1, fatty-acid translocase (FAT)/CD36, and fatty-acid binding proteins. Unlike other FA transporters, the functions of FATPs have been controversial because they contain both motifs of FA transport and fatty acyl-CoA synthetase (ACS). The widely distributed FATP4 is not a direct FA transporter but plays a predominant function as an ACS. FATP4 deficiency causes ichthyosis premature syndrome in mice and humans associated with suppression of polar lipids but an increase in neutral lipids including triglycerides (TGs). Such a shift has been extensively characterized in enterocyte-, hepatocyte-, and adipocyte-specific Fatp4-deficient mice. The mutants under obese and non-obese fatty livers induced by different diets persistently show an increase in blood non-esterified free fatty acids and glycerol indicating the lipolysis of TGs. This review also focuses on FATP4 role on regulatory networks and factors that modulate FATP4 expression in metabolic tissues including intestine, liver, muscle, and adipose tissues. Metabolic disorders especially regarding blood lipids by FATP4 deficiency in different cell types are herein discussed. Our results may be applicable to not only patients with FATP4 mutations but also represent a model of dysregulated lipid homeostasis, thus providing mechanistic insights into obesity and development of fatty liver disease.
... Two lines of Acsl5 -/mice have been developed. 34,35 These mice, similar to Tm6sf2 -/rodents, have reduced VLDL-TG secretion. However, these mice do not accumulate hepatic TG. 35 It is possible that other member of the ACSL family compensate for the absence of ACSL5 in the Acsl5 -/mice. ...
BACKGROUND & AIMS
TM6SF2(E167K) is associated with fatty liver disease and reduced plasma lipid levels. Tm6sf2-/- mice replicate the human phenotype but were not suitable for detailed mechanistic studies. As an alternative model, we generated Tm6sf2-/- rats to determine the subcellular location and function of TM6SF2.
METHODS
Two lines of Tm6sf2-/- rats were established using CRISPR/Cas9 technology. Lipids from tissues and from newly secreted VLDL were quantified using enzymatic assays and mass spectrometry. Neutral lipids were visualized in tissue sections using Oil Red O staining. The rate of dietary triglyceride (TG) absorption, and hepatic VLDL-TG secretion were compared. in Tm6sf2-/- mice and in their WT littermates. The intracellular location of TM6SF2 was determined by cell fractionation. Finally, TM6SF2 was immunoprecipitated from liver and enterocytes to identify interacting proteins.
RESULTS
Tm6sf2-/- rats had a 6-fold higher mean hepatic TG content (56.1±28.9 9 vs. 9.8±3.9 mg/g, P<0.0001) and lower plasma cholesterol levels (99.0±10.5 vs. 110.6±14.0 mg/dL, P=0.0294) than WT littermates. Rates of appearance of dietary and hepatic TG into blood were significantly reduced in Tm6sf2-/- rats (P<0.001 and 0.01, respectively). Lipid content of newly secreted VLDL isolated from perfused livers was reduced 53% (TG) and 62% (cholesterol) (P=0.005 and P=0.01, respectively) in Tm6sf2-/- mice. TM6SF2 was present predominantly in the smooth endoplasmic reticulum (ER) and ER-Golgi intermediate compartments (ERGIC), but not in Golgi. Both ApoB-48 and Acyl-CoA Synthetase Long Chain Family Member 5 (ACSL5) physically interacted with TM6SF2.
CONCLUSIONS
TM6SF2 acts in the SER to promote bulk lipidation of ApoB-containing lipoproteins, thus preventing fatty liver disease.
... 7 Studies from knockout mice suggest that 60%-80% of the total intestinal long chain fatty acyl-CoA synthetase activity is contributed by Acsl5. 8,9 Phenotypes reported from the knockout mice have included increased insulin sensitivity, delayed fat absorption and decreased circulating HDL cholesterol, but no acute postnatal complications have been described. 9,10 In vitro, overexpression of ACSL5 in hepatoma cells caused an increase in fatty acid uptake. ...
... ACSL5 is an abundantly expressed enzyme in the small intestine, and it likely contributes the major long-chain fatty acyl-Co synthetase activity of duodenal enterocytes. 8,9 The obvious primary function of enterocyte ACSL5 is presumably the esterification of fatty acids derived from the intestinal lumen so that new triglycerides may be synthesized and incorporated into chylomicrons for distribution to the liver and other tissues. A lack of ACSL5 would probably cause not only a decrease in the synthesis of triglycerides but also a corresponding increase of non-esterified fatty acids, which would, in turn, cause a variety of harmful lipotoxic effects like inflammation, insulin resistance, ER stress and others. ...
... 9,10 A third study reported no significant differences however. 8 Lipid profiles in our patients showed normal triglycerides but borderline low cholesterol levels. ...
Failure to thrive (FTT) causes significant morbidity, often without clear etiologies. Six individuals of a large consanguineous family presented in the neonatal period with recurrent vomiting and diarrhea, leading to severe FTT. Standard diagnostic work up did not ascertain an etiology. Autozygosity mapping and whole exome sequencing identified homozygosity for a novel genetic variant of the long chain fatty acyl‐CoA synthetase 5 (ACSL5) shared among the affected individuals (NM_203379.1:c.1358C>A:p.(Thr453Lys)). Autosomal recessive genotype–phenotype segregation was confirmed by Sanger sequencing. Functional in vitro analysis of the ACSL5 variant by immunofluorescence, western blotting and enzyme assay suggested that Thr453Lys is a loss‐of‐function mutation without any remaining activity. ACSL5 belongs to an essential enzyme family required for lipid metabolism and is known to contribute the major activity in the mouse intestine. Based on the function of ACSL5 in intestinal long chain fatty acid metabolism and the gastroenterological symptoms, affected individuals were treated with total parenteral nutrition or medium‐chain triglyceride‐based formula restricted in long‐chain triglycerides. The patients responded well and follow up suggests that treatment is only required during early life.
... It is likely that other ACSLs play a role in activating FA for TAG synthesis in the intestine, as also previously proposed to explain the lack of any effect on TAG synthesis in enterocytes after Acsl5 knockout in mice [93]. In mouse jejunum, Acsl5 and Acsl1 were the only expressed isoform with Acsl5 being > 20-fold higher expressed than Acsl1 [116]. In bovine, ACSL1 and ACSL5 have similar transcription level and are the most abundant ACSL isoforms in jejunum (Fig. 1). ...
High producing dairy cows generally receive in the diet up to 5–6% of fat. This is a relatively low amount of fat in the diet compared to diets in monogastrics; however, dietary fat is important for dairy cows as demonstrated by the benefits of supplementing cows with various fatty acids (FA). Several FA are highly bioactive, especially by affecting the transcriptome; thus, they have nutrigenomic effects. In the present review, we provide an up-to-date understanding of the utilization of FA by dairy cows including the main processes affecting FA in the rumen, molecular aspects of the absorption of FA by the gut, synthesis, secretion, and utilization of chylomicrons; uptake and metabolism of FA by peripheral tissues, with a main emphasis on the liver, and main transcription factors regulated by FA. Most of the advances in FA utilization by rumen microorganisms and intestinal absorption of FA in dairy cows were made before the end of the last century with little information generated afterwards. However, large advances on the molecular aspects of intestinal absorption and cellular uptake of FA were made on monogastric species in the last 20 years. We provide a model of FA utilization in dairy cows by using information generated in monogastrics and enriching it with data produced in dairy cows. We also reviewed the latest studies on the effects of dietary FA on milk yield, milk fatty acid composition, reproduction, and health in dairy cows. The reviewed data revealed a complex picture with the FA being active in each step of the way, starting from influencing rumen microbiota, regulating intestinal absorption, and affecting cellular uptake and utilization by peripheral tissues, making prediction on in vivo nutrigenomic effects of FA challenging.
... www.nature.com/scientificreports/ compensated by residual ACSL activity 41 . Long chain fatty acid absorption occurs largely through the jejunum where LCFA are absorbed across the brush border of jejunal enterocytes. ...
... Long chain fatty acid absorption occurs largely through the jejunum where LCFA are absorbed across the brush border of jejunal enterocytes. ACSL5 is expressed in brown adipose tissue, small intestine, liver 27,28,[42][43][44] and is the primary activator of dietary LCFA in the jejunum 41 . Expression, synthesis and activity of ACSL5 is connected to the state of villus architecture, epithelial homeostasis and enterocyte apoptosis [45][46][47] . ...
Inborn errors of metabolism are genetic conditions that can disrupt intermediary metabolic pathways and cause defective absorption and metabolism of dietary nutrients. In an Australian Kelpie breeding population, 17 puppies presented with intestinal lipid malabsorption. Juvenile dogs exhibited stunted postnatal growth, steatorrhea, abdominal distension and a wiry coat. Using genome-wide association analysis, an associated locus on CFA28 (Praw = 2.87E−06) was discovered and validated in a closely related population (Praw = 1.75E−45). A 103.3 kb deletion NC_006610.3CFA28:g.23380074_23483377del, containing genes Acyl-CoA Synthetase Long Chain Family Member 5 (ACSL5) and Zinc Finger DHHC-Type Containing 6 (ZDHHC6), was characterised using whole transcriptomic data. Whole transcriptomic sequencing revealed no expression of ACSL5 and disrupted splicing of ZDHHC6 in jejunal tissue of affected Kelpies. The ACSL5 gene plays a key role in long chain fatty acid absorption, a phenotype similar to that of our affected Kelpies has been observed in a knockout mouse model. A PCR-based diagnostic test was developed and confirmed fully penetrant autosomal recessive mode of inheritance. We conclude the structural variant causing a deletion of the ACSL5 gene is the most likely cause for intestinal lipid malabsorption in the Australian Kelpie.
... Lipidomic profiling of ACSL6 KO mice revealed (20:4), in differentiating spermatids. This type of change is not observed in the KO mice for other ACSL family members (10,(37)(38)(39)(40)(41), suggesting that ACSL6 has selectivity for chain length and double bonds in PUFA structures in vivo. Indeed, the total ACS activity was significantly reduced for DHA and DPA, whereas no change was observed for palmitate and AA in ACSL6 KO testis. ...
Long‐chain polyunsaturated fatty acids (LCPUFAs), such as docosahexaenoic acid (DHA, 22:6) and docosapentaenoic acid (DPA, 22:5), have versatile physiologic functions. Studies have suggested that DHA and DPA are beneficial for maintaining sperm quality. However, their mechanisms of action are still unclear because of the poor understanding of DHA/DPA metabolism in the testis. DHA and DPA are mainly stored as LCPUFA‐containing phospholipids and support normal spermatogenesis. Long‐chain acyl‐conenzyme A (CoA) synthetase (ACSL) 6 is an enzyme that preferentially converts LCPUFA into LCPUFA‐CoA. Here, we report that ACSL6 knockout (KO) mice display severe male infertility due to attenuated sperm numbers and function. ACSL6 is highly expressed in differentiating spermatids, and ACSL6 KO mice have reduced LCPUFA‐containing phospholipids in their spermatids. Delayed sperm release and apoptosis of differentiated spermatids were observed in these mice. The results of this study indicate that ACSL6 contributes to the local accumulation of DHA‐ and DPA‐containing phospholipids in spermatids to support normal spermatogenesis.—Shishikura, K., Kuroha, S., Matsueda, S., Iseki, H., Matsui, T., Inoue, A., Arita, M. Acyl‐CoA synthetase 6 regulates long‐chain polyunsaturated fatty acid composition of membrane phospholipids in spermatids and supports normal spermatogenic processes in mice. FASEB J. 33, 14194‐14203 (2019). www.fasebj.org
