Liver fatty acid binding protein (L‐Fabp) modulates lipid trafficking in enterocytes, hepatocytes, and hepatic stellate cells (HSCs). We examined hepatocyte vs. HSC L‐Fabp deletion in hepatic metabolic adaptation and fibrotic injury. Floxed L‐Fabp mice were bred to different transgenic Cre mice or injected with adeno‐associated virus type 8 (AAV8) Cre and fed diets to promote steatosis and fibrosis or were subjected to either bile duct ligation or CCl4 injury. Albumin‐Cre‐mediated L‐Fabp deletion revealed recombination in hepatocytes and HSCs; these findings were confirmed with 2 other floxed alleles. Glial fibrillary acid protein‐Cre and platelet‐derived growth factor receptor β‐Cre‐mediated L‐Fabp deletion demonstrated recombination only in HSCs. Mice with albumin promoter‐driven Cre recombinase (Alb‐Cre)‐mediated or AAV8‐mediated L‐Fabp deletion were protected against food withdrawal‐induced steatosis. Mice with Alb‐Cre‐mediated L‐Fabp deletion were protected against high saturated fat‐induced steatosis and fibrosis, phenocopying germline L‐Fabp−/− mice. Mice with HSC‐specific L‐Fabp deletion exhibited retinyl ester depletion yet demonstrated no alterations in fibrosis. On the other hand, fibrogenic resolution after CCl4 administration was impaired in mice with Alb‐Cre‐mediated L‐Fabp deletion. These findings suggest cell type‐specific roles for L‐Fabp in mitigating hepatic steatosis and in modulating fibrogenic injury and reversal.—Newberry, E. P., Xie, Y., Lodeiro, C., Solis, R., Moritz, W., Kennedy, S., Barron, L., Onufer, E., Alpini, G., Zhou, T., Blaner, W. S., Chen, A., Davidson, N. O. Hepatocyte and stellate cell deletion of liver fatty acid binding protein reveal distinct roles in fibrogenic injury. FASEB J. 33, 4610–4625 (2019). http://www.fasebj.org

Surgical technique and technology frequently coevolve. The brief history of blood vessel anastomosis is full of famous names. While the techniques pioneered by these surgeons have been well described, the technology that facilitated their advancements and their inventors deserve recognition. The mass production of laboratory microscopes in the mid-1800s allowed for an explosion of interest in tissue histology. This improved understanding of vascular physiology and thrombosis laid the groundwork for Carrel and Guthrie to report some of the first successful vascular anastomoses. In 1916, McLean discovered heparin. Twenty-four years later, Gordon Murray found that it could prevent thrombosis when performing end-to-end anastomosis. These discoveries paved the way for the first-in-human kidney transplantations. Otolaryngologists Nylen and Holmgren were the first to bring the laboratory microscope into the operating room, but Jacobson was the first to apply these techniques to microvascular anastomosis. His first successful attempt in 1960 and the subsequent development of microsurgical tools allowed for an explosion of interest in microsurgery, and several decades of innovation followed. Today, new advancements promise to make microvascular and vascular surgery faster, cheaper, and safer for patients. The future of surgery will always be inextricably tied to the creativity and vision of its innovators.

Increased neuronal excitability contributes to amyloid-β (Aβ) production and aggregation in the Alzheimer's disease (AD) brain. Previous work from our lab demonstrated that hyperglycemia, or elevated blood glucose levels, increased brain excitability and Aβ release potentially through inward rectifying, ATP-sensitive potassium (KATP) channels. KATP channels are present on several different cell types and help to maintain excitatory thresholds throughout the brain. KATP channels are sensitive to changes in the metabolic environment, which are coupled to changes in cellular excitability. Therefore, we hypothesized that neuronal KATP channels are necessary for the hyperglycemic-dependent increases in extracellular Aβ and eliminating KATP channel activity will uncouple the relationship between metabolism, excitability, and Aβ pathology. First, we demonstrate that Kir6.2/KCNJ11, the pore forming subunits, and SUR1/ABCC8, the sulfonylurea receptors, are predominantly expressed on excitatory and inhibitory neurons in the human brain and that cortical expression of KCNJ11 and ABCC8 change with AD pathology in humans and rodent models. Next, we crossed APP/PS1 mice with Kir6.2 -/- mice, which lack neuronal KATP channel activity, to define the relationship between KATP channels, Aβ, and hyperglycemia. Using in vivo microdialysis and hyperglycemic clamps, we explored how acute elevations in peripheral blood glucose levels impacted hippocampal interstitial fluid (ISF) glucose, lactate, and Aβ levels in APP/PS1 mice with or without KATP channels. Kir6.2+/+, APP/PS1 mice and Kir6.2-/-, APP/PS1 mice were exposed to a high sucrose diet for 6 months to determine the effects of chronic hyperglycemia on Aβ deposition. We found that elevations in blood glucose levels correlate with increased ISF Aβ, amyloidogenic processing of amyloid precursor protein (APP), and amyloid plaque pathology in APP/PS mice with intact KATP channels. However, neither acute hyperglycemia nor chronic sucrose overconsumption raised ISF Aβ or increased Aβ plaque burden in APP/PS1 mice lacking Kir6.2-KATP channel activity. Mechanistic studies demonstrate ISF glucose not only correlates with ISF Aβ but also ISF lactate. Without KATP channel activity, ISF lactate does not increase during hyperglycemia, which correlates with decreased monocarboxylate transporter 4 (MCT4) expression, a lactate transporter responsible for astrocytic lactate release. This suggests that KATP channel activity regulates ISF lactate during hyperglycemia, which is important for Aβ release and aggregation. These studies identify a new role for Kir6.2-KATP channels in Alzheimer's disease pathology and suggest that pharmacological antagonism of Kir6.2-KATP channels holds therapeutic promise in reducing Aβ pathology, especially in diabetic and prediabetic patients.

The mechanisms by which alterations in intestinal bile acid (BA) metabolism improve systemic glucose tolerance and hepatic metabolic homeostasis are incompletely understood. We examined metabolic adaptations in mice with conditional intestinal deletion of the abetalipoproteinemia (ABL) gene microsomal triglyceride transfer protein (Mttp-IKO), which blocks chylomicron assembly and impairs intestinal lipid transport. Mttp-IKO mice exhibit improved hepatic glucose metabolism and augmented insulin signaling, without weight loss. These adaptations included decreased BA excretion, increased pool size, altered BA composition, and increased fibroblast growth factor 15 production. Mttp-IKO mice absorb fructose normally but are protected against dietary fructose-induced hepatic steatosis, without weight loss or changes in energy expenditure. In addition, Mttp-IKO mice exhibit altered cecal microbial communities, both at baseline and following fructose feeding, including increased abundance of Bacteroides and Lactobacillus genera. Transplantation of cecal microbiota from chow-fed Mttp-IKO mice into antibiotic-treated wild-type recipients conferred transmissible protection against fructose-induced hepatic steatosis in association with a bloom in Akkermansia and increased Clostridium XIVa genera, whose abundance was positively correlated with fecal coprostanol and total neutral sterol excretion in recipient mice. However, antibiotic-treated Mttp-IKO mice were still protected against fructose-induced hepatic steatosis, suggesting that changes in microbiota are not required for this phenotype. Nevertheless, we found increased abundance of fecal Akkermansia from two adult ABL subjects with MTTP mutations compared to their heterozygous parents and within the range noted in six healthy control subjects. Furthermore, Akkermansia abundance across all subjects was positively correlated with fecal coprostanol excretion. Conclusion: The findings collectively suggest multiple adaptive pathways of metabolic regulation following blocked chylomicron assembly, including shifts in BA signaling and altered microbial composition that confer a transmissible phenotype.

Conflict of interest: SLM served as a consultant for Denali Therapeutics. DMH cofounded and is on the scientific advisory board of C2N Diagnostics. DMH is on the scientific advisory board of Denali, Genentech, and Cajal Neurosciences and consults for Alector.