BackgroundJaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated the molecular mechanisms of bile metabolism, hepatocellular transport, bile ductular development, intestinal bile salt reabsorption, and the regulation of bile acids homeostasis.Main bodyThe major genetic diseases causing jaundice involve disturbances of bile flow. The insufficiency of bile salts in the intestines leads to fat malabsorption and fat-soluble vitamin deficiencies. Accumulation of excessive bile acids and aberrant metabolites results in hepatocellular injury and biliary cirrhosis. Progressive familial intrahepatic cholestasis (PFIC) is the prototype of genetic liver diseases manifesting jaundice in early childhood, progressive liver fibrosis/cirrhosis, and failure to thrive. The first three types of PFICs identified (PFIC1, PFIC2, and PFIC3) represent defects in FIC1 (ATP8B1), BSEP (ABCB11), or MDR3 (ABCB4). In the last 5 years, new genetic disorders, such as TJP2, FXR, and MYO5B defects, have been demonstrated to cause a similar PFIC phenotype. Inborn errors of bile acid metabolism also cause progressive cholestatic liver injuries. Prompt differential diagnosis is important because oral primary bile acid replacement may effectively reverse liver failure and restore liver functions. DCDC2 is a newly identified genetic disorder causing neonatal sclerosing cholangitis. Other cholestatic genetic disorders may have extra-hepatic manifestations, such as developmental disorders causing ductal plate malformation (Alagille syndrome, polycystic liver/kidney diseases), mitochondrial hepatopathy, and endocrine or chromosomal disorders. The diagnosis of genetic liver diseases has evolved from direct sequencing of a single gene to panel-based next generation sequencing. Whole exome sequencing and whole genome sequencing have been actively investigated in research and clinical studies. Current treatment modalities include medical treatment (ursodeoxycholic acid, cholic acid or chenodeoxycholic acid), surgery (partial biliary diversion and liver transplantation), symptomatic treatment for pruritus, and nutritional therapy. New drug development based on gene-specific treatments, such as apical sodium-dependent bile acid transporter (ASBT) inhibitor, for BSEP defects are underway.Short conclusionUnderstanding the complex pathways of jaundice and cholestasis not only enhance insights into liver pathophysiology but also elucidate many causes of genetic liver diseases and promote the development of novel treatments.

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Insulin resistance (IR) is a predisposed condition of type 2 diabetes and commonly leads to fatty liver, in which hepatocytes exhibit excessive lipogenesis and gluconeogenesis. The role of microRNAs (miR) in liver‐associated IR remains largely unknown. Among microRNAs that participate in metabolic signaling, miR‐27b is a critical regulator of lipogenesis in both liver and adipose tissues; however, it is not clear if dysregulation of miR‐27b contributes to IR in liver. To address this question, we established several IR experimental models, including palmitate‐treated mouse AML12 hepatocytes, and dietary‐induced mouse fatty liver; Interestingly, miR‐27b was upregulated in all of these IR models. Furthermore, bioinformatic analysis predicted that miR‐27b targets several genes involved in Akt phosphorylation, including Pdpk1, Pik3ca (P110), Pik3r1 (P85), and Pik3cd. Based on these data, we hypothesize that miR‐27b over‐expression results in defective Akt signaling upon insulin stimulation. Indeed, over‐expression of miR‐27 in human HepaRG liver cells and mouse primary hepatocytes significantly suppressed Akt phosphorylation at both T308 and S473 residues and down‐regulated Pdpk1, Pik3r1 (P85), and Pik3ca (P110) at protein level upon insulin stimulation. Our luciferase reporter assay using 3T3 cells further demonstrated that miR‐27 directly targeted Pdpk1 and Pik3r1 3′UTR. Next, we investigated the mechanism by which miR‐27 is regulated in insulin signaling. Interestingly, we found that insulin significantly reduced miR‐27 expression below 50% of control in both HepaRG and AML12 cells. Further study on the detail mechanisms revealed that miR‐27b expression is positively regulated by cAMP response element‐binding protein (CREB), which is an IR promoter and regulated by insulin. Using HepaRG and AML12 cells, we demonstrated that miR‐27 is significantly down‐regulated by siRNA‐ or metformin‐mediated knockdown of CREB, but up‐regulated by forksolin‐induced activation of CREB. Also, miR‐27b is significantly increased when CREB is up‐regulated in mouse livers by either overnight fasting or high‐fat‐diet feeding, whereas decreased when CREB is down‐regulated in livers of mice treated with metformin. Taken together, our in vitro and in vivo data demonstrated that insulin may negatively regulate miR‐27 by repressing CREB transcriptional activity and the abnormal activation of hepatic CREB in IR animals may cause the aberrant elevation of miR‐27b to further decrease insulin sensitivity.Support or Funding InformationThis project is funded by Ministry of Science and Technology in Taiwan (Project#105‐2628‐B‐002 ‐017‐MY3)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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