BuShenKangShuai Tablet Alleviates Hepatic Steatosis via Improving Liver Adiponectin Resistance in ApoE-/- Mice

BuShenKangShuai tablet (BSKS) is a Chinese herbal compound, which has been used to treat nonalcoholic fatty liver disease and cardiovascular diseases in clinic for over four decades. This study intends to explore whether BSKS administration can alleviates hepatic steatosis via improving liver adiponectin resistance in ApoE-/- mice. ApoE-/- mice were fed with western-type diet for 6 weeks and then were administrated with BSKS or atorvastatin for 6 weeks by gavage, and then blood and liver were collected for analysis. The results showed that BSKS attenuated hepatic steatosis, decreased blood lipids, and increased the serum level of adiponectin. We also found that adiponectin resistance in the liver was improved by BSKS, while the expression of TLR4 and NF-κB p65 was inhibited, followed by the suppression of proinflammatory mediators of TNF-α. Our data provided evidence that BSKS was able to alleviate hepatic steatosis in vivo. The underlying mechanism of BSKS was focused on improving liver adiponectin resistance, thereby regulating dyslipidemia and inhibiting inflammatory signaling pathway.

Tumor necrosis factor-α impairs adiponectin signalling, mitochondrial biogenesis, and myogenesis in primary human myotubes cultures

Skeletal muscle metabolic changes are common in patients with chronic heart failure (HF). Previously, we demonstrated a functional skeletal muscle adiponectin resistance in HF patients with reduced left ventricular ejection fraction (HFrEF). We aimed to examine the impact of adiponectin receptor 1 (AdipoR1) deficiency and TNF-α treatment on adiponectin signaling, proliferative capacity, myogenic differentiation, and mitochondrial biogenesis in primary human skeletal muscle cells. Primary cultures of myoblasts and myotubes were initiated from the musculus vastus lateralis of 10 HFrEF patients (left ventricular ejection fraction; 31.30 ± 2.89%) and 10 age- and gender-matched healthy controls. Healthy control cultures were transfected with siAdipoR1 and/or exposed to TNF-α (10 ng/ml; 72 h). Primary cultures from HFrEF patients preserved the features of adiponectin resistance in vivo. AdipoR1 mRNA was negatively correlated with time to reach maximal cell index ( r = −0.7319, P = 0.003). SiRNA-mediated AdipoR1 silencing reduced pAMPK ( P < 0.01), AMPK activation ( P = 0.046), and myoblast proliferation rate (xCELLigence Real-Time Cellular Analysis; P < 0.0001). Moreover, TNF-α decreased the mRNA expression of genes involved in glucose (APPL1, P = 0.0002; AMPK, P = 0.021), lipid (PPARα, P = 0.025; ACADM, P = 0.003), and mitochondrial (FOXO3, P = 0.018) metabolism, impaired myogenesis (MyoD1, P = 0.053; myogenin, P = 0.048) and polarized cytokine secretion toward a growth-promoting phenotype (IL-10, IL-1β, IFN-γ, P < 0.05 for all; Meso Scale Discovery Technology). Major features of adiponectin resistance are retained in primary cultures from the skeletal muscle of HFrEF patients. In addition, our results suggest that an increased inflammatory constitution contributes to adiponectin resistance and confers alterations in skeletal muscle differentiation, growth, and function.