Immunofluorescent staining for galanin in canine pancreatic tissue was performed together with an evaluation of the effects of synthetic galanin on pancreatic output of glucagon, somatostatin, and insulin in pentobarbital-anesthetized dogs. A dense network of galaninlike immunoreactive nerve fibers was visualized in association with the islets of Langerhans and occasional galanin immunoreactive fibers were seen to course through the exocrine parenchyma of dog pancreas. During intravenous infusion of synthetic porcine galanin (25 pmol X kg-1 X min-1) pancreatic glucagon output rapidly doubled, and the output of both somatostatin and insulin decreased by 70%. Because arterial and pancreatic venous catecholamine levels remained unchanged, the effects on hormone secretion were not secondary to activation of the sympathetic nervous system. The direct pancreatic action of galanin was confirmed by infusing a peripherally ineffective dose of galanin (0.25 pmol X kg-1 X min-1) into the pancreatic artery, which also stimulated glucagon (+90%) and suppressed somatostatin (-50%) and insulin (-70%) release. The presence of galaninlike immunoreactive neurons in dog islets, together with the direct action of galanin on pancreatic hormone release, suggest that this recently discovered peptide could serve as an important neuromodulator of endocrine pancreatic function.

Objective Nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of advanced chronic liver disease. The progression of NAFLD, including nonalcoholic steatohepatitis (NASH), has a strong genetic component, and the most robust contributor is the patatin-like phospholipase domain-containing 3 ( PNPLA3 ) rs738409 encoding the 148M protein sequence variant. We hypothesized that suppressing the expression of the PNPLA3 148M mutant protein would exert a beneficial effect on the entire spectrum of NAFLD. Methods We examined the effects of liver-targeted GalNAc 3 -conjugated antisense oligonucleotide (ASO)-mediated silencing of Pnpla3 in a knock-in mouse model in which we introduced the human PNPLA3 I148M mutation. Results ASO-mediated silencing of Pnpla3 reduced liver steatosis ( p = 0.038) in homozygous Pnpla3 148M/M knock-in mutant mice but not in wild-type littermates fed a steatogenic high-sucrose diet. In mice fed a NASH-inducing diet, ASO-mediated silencing of Pnpla3 reduced liver steatosis score and NAFLD activity score independent of the Pnpla3 genotype, while reductions in liver inflammation score ( p = 0.018) and fibrosis stage ( p = 0.031) were observed only in the Pnpla3 knock-in 148M/M mutant mice. These responses were accompanied by reduced liver levels of Mcp1 ( p = 0.026) and Timp2 ( p = 0.007) specifically in the mutant knock-in mice. This may reduce levels of chemokine attracting inflammatory cells and increase the collagenolytic activity during tissue regeneration. Conclusion This study provides the first evidence that a Pnpla3 ASO therapy can improve all features of NAFLD, including liver fibrosis, and suppress the expression of a strong innate genetic risk factor, Pnpla3 148M, which may open up a precision medicine approach in NASH.

We propose that targeting neutrophils and their inflammatory mediators per se is an opportunity that should be explored to identify new effective medical therapies. The overall clinical goal for neutrophil-targeted therapy will be to modulate, but not completely silence, neutrophil activity, thereby abolishing the destructive inflammation with associated acute and chronic tissue damage without compromising host-defense.

No abstract