Abstract
Nonalcoholic fatty liver disease (NAFLD) is caused by ectopic fat accumulation in the liver. NAFLD is associated with hepatic inflammation and oxidative stress, resulting in nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Placental extracts have been used to treat various chronic diseases due to their antioxidative effect. However, the effects of the extracts on the development of NASH have yet to be elucidated. Here, we demonstrated that supplementation with an oral porcine placental extract (PPE) attenuated lipid accumulation and peroxidation, insulin resistance, inflammatory and stress signaling, and fibrogenesis in the liver of NASH model mice fed a high-cholesterol and high-fat diet. The PPE reduced the number of M1-like liver macrophages, but increased the number of anti-inflammatory M2-like macrophages, resulting in a predominance of M2 over M1 macrophage populations in the liver of NASH mice. Accordingly, the PPE suppressed lipopolysaccharide-induced M1 polarization in isolated murine peritoneal macrophages, whereas it facilitated interleukin 4-induced M2 polarization. Furthermore, the PPE reduced the hepatic stellate cell (HSC) activation associated with the attenuated transforming growth factor-β/Smad3 signaling, both in the liver of NASH mice and in RI-T cells, a HSC line. The PPE may be a potential approach to prevent NASH by limiting lipid peroxidation, promoting M2 macrophage polarization, and attenuating HSC activation.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is frequently described as a spectrum of diseases from simple steatosis to nonalcoholic steatohepatitis (NASH) with advanced fibrosis [1]
To determine the effect of the porcine placental extract (PPE) on diet-induced NASH, we fed C57BL/6J mice with normal chow (NC), the CL diet, or the CL diet supplemented with 0.1% (w/w) or 0.3% (w/w) PPE for 15 weeks
The PPE significantly attenuated hepatic steatosis (Figure 1D), and the increase in liver triglyceride (TG) and non-esterified fatty acid (NEFA) levels caused by the CL diet (Figure 1E), plasma TG, total cholesterol (TC), and NEFA levels were not decreased (Table 1)
Summary
Nonalcoholic fatty liver disease (NAFLD) is frequently described as a spectrum of diseases from simple steatosis to nonalcoholic steatohepatitis (NASH) with advanced fibrosis [1]. Along with the development of NASH, oxidative stress and pro-inflammatory cytokines activate immune cells, such as liver macrophages (i.e., Kupffer cells) and T-lymphocytes Activation of these immune cells results in chronic inflammation and insulin resistance in the liver [4,5,6,7,8]. Our previous study developed a cholesterol- and saturated fatty acid-induced mouse model of lipotoxic NASH, replicating the pathophysiological features of human NASH [8, 9]. The liver of this model mouse exhibits excessive lipid accumulation and aberrant activation of liver macrophages and hepatic stellate cells (HSCs), resulting in the exacerbation of hepatic insulin resistance, inflammation, and fibrosis [9]
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