PT - JOURNAL ARTICLE AU - Alisa K. Manning AU - Anton Scott Goustin AU - Erica L. Kleinbrink AU - Pattaraporn Thepsuwan AU - Juan Cai AU - Donghong Ju AU - Aaron Leong AU - Miriam S. Udler AU - James Bentley Brown AU - Mark O. Goodarzi AU - Jerome I. Rotter AU - Robert Sladek AU - James B. Meigs AU - Leonard Lipovich TI - A long noncoding RNA, <em>LOC157273</em>, is the effector transcript at the chromosome 8p23.1-<em>PPP1R3B</em> metabolic traits and type 2 diabetes risk locus AID - 10.1101/2020.03.24.000620 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.03.24.000620 4099 - http://biorxiv.org/content/early/2020/03/24/2020.03.24.000620.short 4100 - http://biorxiv.org/content/early/2020/03/24/2020.03.24.000620.full AB - Aims Causal transcripts at genomic loci associated with type 2 diabetes are mostly unknown. The chr8p23.1 variant rs4841132, associated with an insulin resistant diabetes risk phenotype, lies in the second exon of a long non-coding RNA (lncRNA) gene, LOC157273, located 175 kilobases from PPP1R3B, which encodes a key protein regulating insulin-mediated hepatic glycogen storage in humans. We hypothesized that LOC157273 regulates expression of PPP1R3B in human hepatocytes.Methods We tested our hypothesis using Stellaris fluorescent in-situ hybridization to assess subcellular localization of LOC157273; siRNA knockdown of LOC157273, followed by RT-PCR to quantify LOC157273 and PPP1R3B expression; RNA-seq to quantify the whole-transcriptome gene expression response to LOC157273 knockdown and an insulin-stimulated assay to measure hepatocyte glycogen deposition before and after knockdown.Results We found that siRNA knockdown decreased LOC157273 transcript levels by approximately 80%, increased PPP1R3B mRNA levels by 1.7-fold and increased glycogen deposition by &gt;50% in primary human hepatocytes. An A/G heterozygous carrier (vs. three G/G carriers) had reduced LOC157273 abundance due to reduced transcription of the A allele and increased PPP1R3B expression and glycogen deposition.Conclusion We show that the lncRNA LOC157273 is a negative regulator of PPP1R3B expression and glycogen deposition in human hepatocytes and the causal transcript at an insulin resistant type 2 diabetes risk locus.