A
            <i>LIMA1</i>
            variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption

Zhang, Yingyu; Fu, Zhen-Yan; Wei, Jian; Qi, Wei; Baituola, Gulinaer; Luo, Jie; Meng, Yuanjing; Guo, Shuyuan; Yin, Huiyong; Jiang, Shi-You; Li, Yunfeng; Miao, Hong‐Hua; Liu, Yong; Wang, Yan; Li, Bo-Liang; Ma, Yun; Song, Bao-Liang

doi:10.1126/science.aao6575

Cited by 123 publications

(87 citation statements)

References 45 publications

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“…Fecal triglyceride, serum triglyceride, and free fatty acid measurements Fecal triglyceride was measured as described previously [40]. Briefly, feces were collected, freeze-dried, and ground to powder.…”

Section: Metabolic Parameter Measurementsmentioning

confidence: 99%

Short‐term tamoxifen treatment has long‐term effects on metabolism in high‐fat diet‐fed mice with involvement of Nmnat2 in POMC neurons

et al. 2018

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Short-term tamoxifen treatment has effects on lipid and glucose metabolism in mice fed chow. However, its effects on metabolism in mice fed high-fat diet (HFD) and the underlying mechanisms are unclear. Here, we show that tamoxifen treatment for 5 days decreases fat mass for as long as 18 weeks in mice fed HFD. Tamoxifen alters mRNA levels of some genes involved in lipid metabolism in white adipose tissue and improves glucose and insulin tolerance as well as hepatic insulin signaling for 12-20 weeks. Proopiomelanocortin (POMC) neuron-specific deletion of nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) attenuates the effects of tamoxifen on glucose and insulin tolerance. These data demonstrate that short-term injection of tamoxifen has long-term effects on lipid and glucose metabolism in HFD mice with involvement of Nmnat2 in POMC neurons.

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Section: Metabolic Parameter Measurementsmentioning

confidence: 99%

Short‐term tamoxifen treatment has long‐term effects on metabolism in high‐fat diet‐fed mice with involvement of Nmnat2 in POMC neurons

et al. 2018

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“…GWAS has been performed extensively on blood lipids traits and more than 300 risk loci were found in different populations 5 . These loci cover almost all the well-known genes that are important in lipid metabolism, such as LDLR 6 , ARH 7 , ABCA1 8 , ABCG5/G8 9 , PCSK9 10 , NPC1L1 11,12 , LIMA1 13 , et al Although GWAS is a powerful approach, we find that about 2/3 of these risk loci are located in noncoding regions and are not close to any gene known plays a role in lipid metabolism. The disease-causing variants in these loci and their underlying molecular mechanism remain largely unknown, which prevent the interpretation of the GWAS results and their application in precise medicine.…”

Section: Figure 1mentioning

confidence: 73%

Hypercholesterolemia risk associated GPR146 is an orphan G-protein coupled receptor that regulates blood cholesterol level in human and mouse

Han

Liu

Chen

et al. 2020

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14 15 2 Genome-wide association studies (GWAS) have identified hundreds of genetic variants 16 associated with dyslipidemia. However, about 95% of of these variants are located in genome 17 noncoding regions and cluster in different loci. The disease-causing variant for each locus and 18 underline mechanism remain largely unknown. We systematically analyzed these noncoding 19 variants and found that rs1997243 is the disease-causing variant in locus 7p22, which is 20 strongly associated with hypercholesterolemia. The rs1997243 risk allele is associated with 21 increased expression of GPR146 in human and targeted activation of the rs1997243 site 22 specifically up regulates GPR146 expression in cultured cells. GPR146 is an orphan G-protein 23 coupled receptor that is located on plasma membrane and responses to stimulation of heat-24 inactivated serum. Disrupting gpr146 specifically in the liver decreases the blood cholesterol 25 level and prevents high-fat or high-fat high-cholesterol diets induced hypercholesterolemia in 26 mice. Thus we uncovered a novel G-protein coupled receptor that regulates blood cholesterol 27 level in both human and mouse. Our results also suggest that antagonizing GPR146 function 28 will be an effective strategy to treat hypercholesterolemia. 29Genome-wide association study (GWAS) is a powerful tool to ascertain the contribution of 30 common genetic variants in population-wide diseases variability. Hundreds of GWAS studies have 31 been applied to a variety of diseases or traits including dyslipidemia, diabetes, and hypertension et 32 al 1 . More than 93% of these disease-and trait-associated variants are located in the non-coding 33 regions, makes it difficult to evaluate their function 2 . Previous studies showed that these disease-34 and trait-associated variants are concentrated in regulatory DNA, with about 80% of all noncoding 35 GWAS single nucleotide polymorphisms (SNPs) or linkage disequilibrium (LD) SNPs are located 36 within DNase I hypersensitive sites (DHS) 2 , which suggest that most of these noncoding SNPs 37 3 function through transcriptional regulation. 38Hypercholesterolemia is the leading risk factor for cardiovascular diseases. Current evidence 39 suggests that the heritability for blood cholesterol level is high, with 40-50% for low-density 40 lipoprotein cholesterol (LDL-C) and 40-60% for high-density lipoprotein cholesterol (HDL-C) 3,4 . 41 GWAS has been performed extensively on blood lipids traits and more than 300 risk loci were found 42 in different populations 5 . These loci cover almost all the well-known genes that are important in 43 lipid metabolism, such as LDLR 6 , ARH 7 , ABCA1 8 , ABCG5/G8 9 , PCSK9 10 , NPC1L1 11,12 , LIMA1 13 , 44 et al. Although GWAS is a powerful approach, we find that about 2/3 of these risk loci are located 45 in noncoding regions and are not close to any gene known plays a role in lipid metabolism. The 46 disease-causing variants in these loci and their underlying molecular mechanism remain largely 47

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“…The rs58542926 polymorphic variant of the TM6SF2 gene is used to identify individuals with a higher susceptibility to chronic liver diseases, especially hepatocellular carcinoma, cirrhosis, alcoholic liver disease, and nonalcoholic fatty liver disease [121,122]. LIMA1 encodes a negative regulator of cholesterol absorption, and its mutations lead to a decrease in the LIMA1 protein level [123]. In studies on mice and humans, LIMA1 has been identified as a key protein regulating intestinal cholesterol absorption [124].…”

Section: Discussionmentioning

confidence: 99%

Genes Potentially Associated with Familial Hypercholesterolemia

et al. 2019

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This review addresses the contribution of some genes to the phenotype of familial hypercholesterolemia. At present, it is known that the pathogenesis of this disease involves not only a pathological variant of low-density lipoprotein receptor and its ligands (apolipoprotein B, proprotein convertase subtilisin/kexin type 9 or low-density lipoprotein receptor adaptor protein 1), but also lipids, including sphingolipids, fatty acids, and sterols. The genetic cause of familial hypercholesterolemia is unknown in 20%–40% of the cases. The genes STAP1 (signal transducing adaptor family member 1), CYP7A1 (cytochrome P450 family 7 subfamily A member 1), LIPA (lipase A, lysosomal acid type), ABCG5 (ATP binding cassette subfamily G member 5), ABCG8 (ATP binding cassette subfamily G member 8), and PNPLA5 (patatin like phospholipase domain containing 5), which can cause aberrations of lipid metabolism, are being evaluated as new targets for the diagnosis and personalized management of familial hypercholesterolemia.

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A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption

Cited by 123 publications

References 45 publications

Short‐term tamoxifen treatment has long‐term effects on metabolism in high‐fat diet‐fed mice with involvement of Nmnat2 in POMC neurons

Short‐term tamoxifen treatment has long‐term effects on metabolism in high‐fat diet‐fed mice with involvement of Nmnat2 in POMC neurons

Hypercholesterolemia risk associated GPR146 is an orphan G-protein coupled receptor that regulates blood cholesterol level in human and mouse

Genes Potentially Associated with Familial Hypercholesterolemia

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