Alleviation of Hepatic Steatosis by Alpha-Defensin Is Associated with Enhanced Lipolysis

Abstract

Background and Objectives: The neutrophilic peptide, alpha-defensin, is considered an evolving risk factor intimately linked with lipid mobilization. It was previously linked to augmented liver fibrosis. Here, we assess a potential association between alpha-defensin and fatty liver. Materials and Methods: A cohort of transgenic C57BL/6JDef+/+ male mice that overexpress the human neutrophil-derived alpha-defensin in their polymorphonuclear neutrophils (PMNs) were assessed for liver steatosis and fibrosis development. Wild type (C57BL/6JDef.Wt) and transgenic (C57BL/6JDef+/+) mice were maintained on a standard rodent chow diet for 8.5 months. At the termination of the experiment, systemic metabolic indices and hepatic immunological cell profiling were assessed. Results: The Def+/+ transgenic mice exhibited lower body and liver weights, lower serum fasting glucose and cholesterol, and significantly lower liver fat content. These results were associated with impaired liver lymphocytes count and function (lower CD8, NK cells, and killing marker CD107a). The metabolic cage demonstrated dominant fat utilization with a comparable food intake in the Def+/+ mice. Conclusions: Chronic physiological expression of alpha-defensin induces favorable blood metabolic profile, increased systemic lipolysis, and decreased hepatic fat accumulation. Further studies are needed to characterize the defensin net liver effect.

Human Neutrophil Alpha-Defensins Promote NETosis and Liver Injury in Alcohol-Related Liver Cirrhosis: Potential Therapeutic Agents

“…The deregulation of PPAR pathways leads to the development of non-alcoholic fatty liver disease (NAFLD), ALD, hepatitis virus-injury, and HCC [ 41 , 42 ]. The chronic expression of alpha-defensins induces increased systemic lipolysis and decreased hepatic fat accumulation [ 43 ]. In particular, the defensins neutralize bacterial toxins, disrupt the membrane of the bacterial cell wall, and inhibit the synthesis of the bacterial cell wall leading to killing bacteria or preventing their growth [ 7 ].…”

The relevance of intestinal barrier dysfunction, antimicrobial proteins and bacterial endotoxin in metabolic dysfunction‐associated steatotic liver disease

“…104 In addition to intestinal defensins, the induction of systemic αdefensin, by its overexpression in polymorphonuclear leukocytes, also exhibit important benefits in the prevention of MASLD by improving lipid metabolism and attenuating liver fat accumulation. 105…”

“…Additionally, administration of full‐length human α‐defensin 5 to high fat diet (HFD)‐fed mice during 10 weeks displayed a positive role attenuating dyslipidemia and circulating free fatty acid levels, 102 and administration of human β‐defensin 2 exerted hepatic protective effects, as reflected by improving alcohol‐related liver disease and reducing plasma alanine transaminase activity in mice fed with an ethanol‐containing diet 104 . In addition to intestinal defensins, the induction of systemic α‐defensin, by its overexpression in polymorphonuclear leukocytes, also exhibit important benefits in the prevention of MASLD by improving lipid metabolism and attenuating liver fat accumulation 105 …”

Transcriptomic (DNA Microarray) and Metabolome (LC-TOF-MS) Analyses of the Liver in High-Fat Diet Mice after Intranasal Administration of GALP (Galanin-like Peptide)

“…Defensins production is induced by infectious stimuli but also by inflammation [93]. Recently, the chronic inflammatory inhibitory effect of defensins has been proposed for the treatment of diabetic wounds [94], and α-defensins have been found to induce a favorable blood metabolic profile, increased systemic lipolysis, and decreased liver fat accumulation [95].…”