Additional Supporting Information may be found in the online version of this article.

HEP_24349_sm_suppinfo.doc37KSupporting Information
HEP_24349_sm_suppinfoFig1.tif1156KSupporting Information Figure S1: The hi559 pancreatic tissue does not exhibit any overt abnormal architecture. (A) Expression of try (exocrine pancreas, arrow, left panel) and ins (endocrine pancreas, arrow, right panel) are similar in wild-type (left) and hi559 larvae (right). (B) H&E staining of sagittal sections (4 μ) through pancreatic region of 5-dpf wild-type and hi559 larvae. Endocrine pancreatic islet is indicated by arrow. The hi559 pancreas does not exhibit any overt defects in its architecture. ep, endocrine pancreas
HEP_24349_sm_suppinfoFig2.tif1585KSupporting Information Figure S2: cdipt morphants phenocopy hi559 phenotype. Embryos injected with p53 morpholino alone appears normal at 6 dpf (panel A), whereas embryos injected with p53 morpholino and two different cdipt splice-blocking morpholinos, cdipt-Mo1 (panel B) and cdipt-Mo2 (panel C) exhibit hepatomegaly, globular-appearing liver and smaller intestine at 6-dpf, resembling hi559 hepatic phenotype. The cdipt morphants survive through 7-dpf, but the liver and intestine exhibit severe defects (panel D). Injection of cdipt mRNA results in significant reduction of larvae showing hi559 phenotype (panel E)
HEP_24349_sm_suppinfoFig3.tif1786KSupporting Information Figure S3: Comparison of cdipt expression in wild-type and hi559 embryos during embryonic development. Developmental expression of cdipt at 1-dpf (A), 2-dpf (B), 3-dpf (C) and 4-dpf (D). Cdipt is expressed in the developing liver (arrow), intestine, brain, eye and branchial arches in wild-type embryos, whereas its expression is negligible in hi559 embryos. Wild-type on top, mutant below in each panel
HEP_24349_sm_suppinfoFig4.tif1354KSupporting Information Figure S4: TLC showing phospholipid profile of the wild-type and hi559 embryos. The PtdIns level (PtdIns band indicated by arrow) of the deyolked 5-dpf wild-type and hi559 larvae is unaltered. Sufficient amount of PtdIns is also present in the yolk (1-cell stage) suggesting maternal deposition of PtdIns in the yolk. The overall phospholipid profile does not differ qualitatively in wild-type and hi559 larvae. CH: Cholesterol, TG: Triglycerides, CB: Cerebrosides, PE: Phosphatidylethenolamine, PA; Phosphatidic Acid, PC: Phosphatidylcholine, PI: Phosphatidylinositol, PS: Phosphatidylserine
HEP_24349_sm_suppinfoFig5.tif846KSupporting Information Figure S5: Chemical inhibition of PIS replicates hi559 phenotype. More than 80% of the wild-type larvae treated with δ-HCH at 10 μM during 3 to 5-dpf exhibit hepatomegaly and a darkish liver (yellow outline) at 5-dpf similar to hi559 (A), and a fatty liver as shown by ORO staining (B). Data are representative of 3 biological clutches. Wild-type on top, mutant below in each panel
HEP_24349_sm_suppinfoFig6.tif2145KSupporting Information Figure S6: Distortion of sinusoid architecture in the hi559 liver. (A) Whole-mount alkaline phosphatase staining reveals abnormality of intrahepatic vasculature in severely steatotic hi559 liver, whereas rest of the larval vasculature appears normal. (B) Sagittal sections of larvae stained with alkaline phosphatase and eosin showing compressed sinusoids in the mutant liver (arrow). Liver is outlined by dotted line. ihv, intrahepatic vessels; isv, intersomitic vessels; siv, subintestinal vein. Scale bars, 20 μM
HEP_24349_sm_suppinfoFig7.tif2107KSupporting Information Figure S7: Pathways showing transcriptional upregulation of ERSR components. ERSR pathway from Ingenuity overlaid with microarray expression values. Color intensity is proportional to fold-change (red, upregulated; blue downregulated; white absent on array)
HEP_24349_sm_suppinfoFig8.tif2576KSupporting Information Figure S8: Diagrammatic representation of the proposed model of cellular mechanisms contributing to ER stress due to disruption of PtdIns synthesis. PtdIns and PI signaling are critical for proper functions of ER, secretory pathways, and ER-associated degradation (ERAD). Thus, we hypothesize that limited de novo PtdIns may affect one or combinations of these cellular processes causing an unresolved chronic ER stress
HEP_24349_sm_suppinfoFig9.tif2019KSupporting Information Figure S9: Zebrafish Cdipt is an orthologue of mammalian CDIPT. Sequence alignment shows striking similarity of the zebrafish Cdipt with its mammalian counterpart

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