Crucial Role of Elovl6 in Chondrocyte Growth and Differentiation during Growth Plate Development in Mice

Kikuchi, Manami; Shimada, Masako; Matsuzaka, Takashi; Ishii, Kiyo‐aki; Nakagawa, Yoshimi; Takayanagi, Misa; Yamada, Nobuhiro; Shimano, Hitoshi

doi:10.1371/journal.pone.0159375

Cited by 9 publications

(5 citation statements)

References 29 publications

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“…ELOVL6 extends the carbon chain of fatty acids and inhibits their use, which may be detrimental in rapid tumor proliferation. Additional studies have confirmed that ELOVL6 is involved in both migration and proliferation (45,46), and in the present study, ELOVL6 expression was associated with vascular invasion, which is also closely associated with factors such as vascular endothelial growth factor. The majority of chronic liver diseases are associated with hypoxic symptoms that come with with metabolic diseases, such as non-alcoholic fatty liver disease.…”

Section: Univariate Analysis Multivariate Analysis ------------------supporting

confidence: 86%

Decreased expression levels of ELOVL6 indicate poor prognosis in hepatocellular carcinoma

Li¹,

Wang²,

Tang³

et al. 2019

Oncol Lett

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The present study aimed to investigate the expression of elongation of very long-chain fatty acids family member 6 (ELOVL6) in hepatocellular carcinoma (HCC) tissues, and to determine its role in the development of HCC. A total of 377 HCC specimens were collected for tissue microarray and immunohistochemistry analyses. The ELOVL6 IHC score for HCC tissues was 0.97±0.71, which was significantly lower than that of the matched adjacent normal tissues (1.32±0.68; P<0.001). Patients with low levels of ELOVL6 expression were older (P=0.014) and possessed larger sized tumors (P=0.039) than patients with high expression levels. Additionally, Kaplan-Meier analysis revealed that patients with low ELOVL6 expression levels also had significantly poorer overall (P<0.001) and disease-free (P=0.029) survival times, and a greater probability of recurrence. The tumor size, tumor-node-metastasis (TNM) stage, vascular invasion and ELOVL6 expression were all shown to be prognostic variables for overall survival in patients with HCC. Multivariate analysis revealed that vascular invasion (P<0.001), TNM stage (P<0.001) and ELOVL6 expression (P=0.001) were independent prognostic variables for overall survival. In addition, vascular invasion (P=0.032) and ELOVL6 expression (P=0.041) were independent risk factors for disease-free survival, and vascular invasion (P=0.019) and ELOVL6 expression (P=0.045) were independent risk factors associated with HCC recurrence. The present study revealed that in patients with HCC, ELOVL6 expression level was reduced in HCC tissues, and that higher ELOVL6 expression levels correlated with longer survival times. This indicates that ELOVL6 may serves as an independent marker of poor patient outcome.

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Section: Univariate Analysis Multivariate Analysis ------------------supporting

confidence: 86%

Decreased expression levels of ELOVL6 indicate poor prognosis in hepatocellular carcinoma

Li¹,

Wang²,

Tang³

et al. 2019

Oncol Lett

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“…However, because Elovl6 deletion was not targeted to the pancreas and was achieved in all tissues, the possibility remains that Elovl6 deletion might affect the FA profile in other tissues to affect overall organismal metabolism and, therefore, b-cell function. Indeed, we previously showed that Elovl6 deficiency altered FA composition in serum and various organs and affected a wide range of cellular functions and the disease progression (19,21,(48)(49)(50). We assume the changes of plasma FA composition might influence the FA composition of islets; however, changes in FA composition of db/db;Elovl6 2/2 islets were different from changes observed in plasma: a marked reduction in oleate component without a reduction in stearate and an increase in palmitate, compared with db/db;Elovl6 +/+ islets.…”

Section: Discussionmentioning

confidence: 99%

Elovl6 Deficiency Improves Glycemic Control in Diabetic db/db Mice by Expanding β-Cell Mass and Increasing Insulin Secretory Capacity

et al. 2017

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Dysfunctional fatty acid (FA) metabolism plays an important role in the pathogenesis of β-cell dysfunction and loss of β-cell mass in type 2 diabetes (T2D). Elovl6 is a microsomal enzyme that is responsible for converting C16 saturated and monounsaturated FAs into C18 species. We previously showed that Elovl6 played a critical role in the development of obesity-induced insulin resistance by modifying FA composition. To further define its role in T2D development, we assessed the effects of deletion in leptin receptor-deficient C57BL/KsJ/ mice, a model of T2D. The /; mice had a markedly increased β-cell mass with increased proliferation and decreased apoptosis, an adaptive increase in insulin, and improved glycemic control. / islets were characterized by a prominent elevation of oleate (C18:1n-9), cell stress, and inflammation, which was completely suppressed by Elovl6 deletion. As a mechanistic ex vivo experiment, isolated islets from mice exhibited reduced susceptibility to palmitate-induced inflammation, endoplasmic reticulum stress, and β-cell apoptosis. In contrast, oleate-treated islets resulted in impaired glucose-stimulated insulin secretion with suppressed related genes irrespective of the Elovl6 gene. Taken together, Elovl6 is a fundamental factor linking dysregulated lipid metabolism to β-cell dysfunction, islet inflammation, and β-cell apoptosis in T2D, highlighting oleate as the potential culprit of β-cell lipotoxicity.

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“…Elovl6 knockout mice are insulin resistant and develop obesity and hepatosteatosis when fed a high fat diet (Matsuzaka et al, 2007), indicating that ELOVL6 is important to normal metabolic regulation. The activity of ELOVL6 can also regulate thermogenic activity in brown fat adipocytes (Tan et al, 2015) and chondrocyte growth (Kikuchi et al, 2016). No direct causal linkage of ELOVL6 mutations to human disease has been established.…”

Section: Introductionmentioning

confidence: 99%

Novel Cellular Functions of Very Long Chain-Fatty Acids: Insight From ELOVL4 Mutations

Deák

Anderson

Fessler

et al. 2019

Front. Cell. Neurosci.

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Elongation of Very Long chain fatty acids-4 (ELOVL4) protein is a member of the ELOVL family of fatty acid elongases that is collectively responsible for catalyzing formation of long chain fatty acids. ELOVL4 is the only family member that catalyzes production of Very Long Chain Saturated Fatty Acids (VLC-SFA) and Very Long Chain Polyunsaturated Fatty Acids (VLC-PUFA) with chain lengths ≥28 carbons. ELOVL4 and its VLC-SFA and VLC-PUFA products are emerging as important regulators of synaptic signaling and neuronal survival in the central nervous system (CNS). Distinct sets of mutations in ELOVL4 cause three different neurological diseases in humans. Heterozygous inheritance of one set of autosomal dominant ELOVL4 mutations that leads to truncation of the ELOVL4 protein causes Stargardt-like macular dystrophy (STGD3), an aggressive juvenile-onset retinal degeneration. Heterozygous inheritance of a different set of autosomal dominant ELOVL4 mutations that leads to a full-length protein with single amino acid substitutions causes spinocerebellar ataxia 34 (SCA34), a late-onset neurodegenerative disease characterized by gait ataxia and cerebellar atrophy. Homozygous inheritance of a different set of ELOVL4 mutations causes a more severe disease with infantile onset characterized by seizures, spasticity, intellectual disability, ichthyosis, and premature death. ELOVL4 is expressed widely in the CNS and is found primarily in neurons. ELOVL4 is expressed in cell-specific patterns within different regions of the CNS that are likely to be related to disease symptoms. In the retina, ELOVL4 is expressed exclusively in photoreceptors and produces VLC-PUFA that are incorporated into phosphatidylcholine and enriched in the light sensitive membrane disks of the photoreceptor outer segments. VLC-PUFA are enzymatically converted into “elovanoid” compounds that appear to provide paracrine signals that promote photoreceptor and neuronal survival. In the brain, the main ELOVL4 products are VLC-SFA that are incorporated into sphingolipids and enriched in synaptic vesicles, where they regulate kinetics of presynaptic neurotransmitter release. Understanding the function of ELOVL4 and its VLC-SFA and VLC-PUFA products will advance our understanding of basic mechanisms in neural signaling and has potential for developing novel therapies for seizure and neurodegenerative diseases.

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Crucial Role of Elovl6 in Chondrocyte Growth and Differentiation during Growth Plate Development in Mice

Cited by 9 publications

References 29 publications

Decreased expression levels of ELOVL6 indicate poor prognosis in hepatocellular carcinoma

Decreased expression levels of ELOVL6 indicate poor prognosis in hepatocellular carcinoma

Elovl6 Deficiency Improves Glycemic Control in Diabetic db/db Mice by Expanding β-Cell Mass and Increasing Insulin Secretory Capacity

Novel Cellular Functions of Very Long Chain-Fatty Acids: Insight From ELOVL4 Mutations

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