Depletion of IQ motif-containing GTPase activating protein 2 (IQGAP2) reduces hepatic glycogen and impairs insulin signaling.

The liver is critical in maintaining metabolic homeostasis, regulating both anabolic and catabolic processes. Scaffold protein IQ motif-containing GTPase activating protein 2 (IQGAP2) is highly expressed in the liver and implicated in fatty acid uptake. However, its role in coordinating either fed or fasted responses is not well understood. Here we report that IQGAP2 is widely expressed in the liver that is pronounced in the pericentral region. Although control and IQGAP2 knockout mouse model showed comparable hepatic gene expression in the fasted state, we found significant defects in fed state responses. Glycogen levels were reduced in the periportal region when IQGAP2 was deleted. Consistently, we observed a decrease in phosphorylated glycogen synthase kinase 3α and total glycogen synthase protein in the fed IQGAP2 knockout mice which suggest inadequate glycogen synthesis. Moreover, immunoprecipitation of IQGAP2 revealed its interaction with GSK3 and GYS. Furthermore, our study demonstrated that knocking down IQGAP2 in vitro significantly decreased the phosphorylation of AKT and forkhead box O3 proteins downstream of insulin signaling. These findings suggest that IQGAP2 contributes to liver fed state metabolism by interacting with glycogen synthesis regulators and affecting the phosphorylation of insulin pathway components. Our results suggest that IQGAP2 plays a role in regulating fed state metabolism.

Deletion of Constitutive Androstane Receptor Led to Intestinal Alterations and Increased Imidacloprid in Murine Liver.

Imidacloprid (IMI) is the most frequently detected neonicotinoid pesticide in the environment. Despite typically low toxicity in vertebrates, IMI exposure is associated with liver and gastrointestinal toxicity. The mechanism underlying IMI toxicity in mammals is unclear. Pesticide exposure frequently activates xenobiotic nuclear receptors, such as the constitutive androstane receptor (CAR), to induce detoxification phase I and phase II genes. This study examined the role of CAR in mediating IMI off-target toxicity. Female Car-/- and wild-type (WT) mice were orally administered imidacloprid (50 mg/kg, twice daily) for 21 days, following which serum, liver, and intestinal tissues were collected. Liver tissue analysis indicated mild inflammation and induction of detoxification gene Cyp2b10 in IMI-exposed WT mice. The absence of CAR increased hepatic IMI accumulation. Microbiome analysis of ileal samples revealed IMI altered microbial diversity in a genotype-specific manner, with increased α-diversity in Car-/- mice while decreased α-diversity in WT mice. We observed Car-/- mice exhibit intestinal alterations with decreased CYP-P450 expression, blunted villi height, and increased small intestine length and weight independent of IMI exposure. Our results suggest that IMI is not overtly toxic. However, the absence of xenobiotic nuclear receptor CAR allows increased accumulation of IMI in the liver and disrupts the villi structure and Cyp gene expression in the intestine.

Jekyll and Hyde: nuclear receptors ignite and extinguish hepatic oxidative milieu.

Nuclear receptors (NRs) are ligand-binding transcription factors that regulate gene networks and physiological responses. Often oxidative stress precedes the onset of liver diseases, and Nrf2 is a key regulator of antioxidant pathways. NRs crosstalk with Nrf2, since NR activation can influence the oxidative milieu by modulating reductive cellular processes. Diet and xenobiotics also regulate NR expression and activity, suggesting a feedback loop. Depending on the tissue context and cues, NRs either increase or decrease toxicity and oxidative damage. Many FDA-approved drugs target NRs, and one could potentially repurpose them to ameliorate reactive oxygen species (ROS). Here, we discuss how several NRs modulate oxidative stress subsequent to diet, organic pollutants, and drug-induced injury to the liver.

Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration.

The liver can substantially regenerate after injury, with both main epithelial cell types, hepatocytes and biliary epithelial cells (BECs), playing important roles in parenchymal regeneration. Beyond metabolic functions, BECs exhibit substantial plasticity and in some contexts can drive hepatic repopulation. Here, we performed single-cell RNA sequencing to examine BEC and hepatocyte heterogeneity during homeostasis and after injury. Instead of evidence for a transcriptionally defined progenitor-like BEC cell, we found significant homeostatic BEC heterogeneity that reflects fluctuating activation of a YAP-dependent program. This transcriptional signature defines a dynamic cellular state during homeostasis and is highly responsive to injury. YAP signaling is induced by physiological bile acids (BAs), required for BEC survival in response to BA exposure, and is necessary for hepatocyte reprogramming into biliary progenitors upon injury. Together, these findings uncover molecular heterogeneity within the ductal epithelium and reveal YAP as a protective rheostat and regenerative regulator in the mammalian liver.