Spermidine Ameliorates Nonalcoholic Steatohepatitis through Thyroid Hormone-Responsive Protein Signaling and the Gut Microbiota-Mediated Metabolism of Bile Acids

Abstract

Spermidine, a natural polyamine and physiological autophagy inducer, is involved in various physiological processes. However, the impact and mechanism of spermidine on nonalcoholic steatohepatitis (NASH) remains unclarified. We found that daily spermidine intake was significantly lower in volunteers with liver dysfunction than the healthy controls, and the serum and fecal spermidine levels were negatively correlated with the NASH phenotypes. Spermidine supplementation significantly attenuated hepatic lipid accumulation, insulin resistance, hepatic inflammation, and fibrosis in NASH mice induced by a western diet. The ameliorating effect of spermidine on lipid accumulation might be partly regulated by thyroid hormone-responsive protein (THRSP) signaling and autophagy. Moreover, spermidine altered the profile of hepatic bile acids (BAs) and microbial composition and function. Furthermore, spermidine reversed the progression of hepatic steatosis, inflammation, and fibrosis in mice with preexisting NASH. Therefore, spermidine ameliorates NASH partly through the THRSP signaling and the gut microbiota-mediated metabolism of BAs, suggesting that spermidine might be a viable therapy for NASH.

Oral Supplementation with the Polyamine Spermidine Affects Hepatic but Not Pulmonary Lipid Metabolism in Lean but Not Obese Mice

“…Studies exploring oral supplementation of spermidine are scarce. Ni et al reported that oral administration of spermidine did not reduce body weights of Western diet-fed animals, but, in contrast, improved serum triglyceride (TG) levels, hepatic steatosis, glucose tolerance and insulin resistance [ 26 ]. In our study, serum TG levels were decreased by spermidine in the HSD-S group in week 29 as well as in the HFD-S group in week 10 ( Figure 4 O,P), pointing to diet- and time-dependent spermidine effects.…”

“…One obvious difference between the study of Ni et al and our study is the different diet systems. While we used either an HFD (35% fat, mainly cholesterol-rich lard) or an HSD (46% sucrose), Ni et al used a Western diet composed of 40% fat, 41% sucrose and 1.25% cholesterol and additionally used fructose/glucose-enriched drinking water [ 26 ]. Therefore, the diet-related metabolic profiles of the mice were likely different.…”

“…Under a high fat diet regimen, a daily intraperitoneal dose of spermine improves glucose utilization and decreases body weights of obese mice, whereas a daily injection of spermidine even led to reduced hepatic steatosis [ 24 , 25 ]. In humans, it was shown that NASH parameters are negatively correlated with spermidine intake and serum levels, whereas in mice the oral supplementation of spermidine was able to ameliorate NASH by regulating the liver lipid metabolism [ 26 ]. Furthermore, increased levels of polyamines in white adipose tissue and the liver might confer resistance to diet-induced obesity and NAFLD [ 27 ].…”

Autophagy: A Cellular Guardian against Hepatic Lipotoxicity

“…Additionally, akebia saponin D (ASD), extracts from Akebia quinata [ 102 ], and capsaicin, an extract of Capsicum annuum [ 103 ], a common dietary supplement, have been shown to exert beneficial effects on NAFLD via autophagy induction. Spermidine, a natural polyamine and health supplement, is a potent autophagy stimulator and counters lipid-induced liver damage via autophagy enhancement [ 104 ]. ω-3 fatty acids present in fish oil, flaxseeds, and walnuts prevent FFA-induced lipotoxicity through induction of autophagy in NAFLD [ 105 ].…”

High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study

“…However, clinical data failed to confirm any positive effects of spermidine on age-related cognitive decline in contrast to preclinical studies, implying a respective effect [28]. The same also applies to the putative role of spermidine in other age-related diseases [8,29], cardiovascular health [30][31][32], nonalcoholic steatohepatitis (NASH) [33], Alzheimer's disease [34], immune functions [35], and ophthalmology [36].…”