Abstract
The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide. Activation of Kupffer cells (KCs) is central to the development of diet-induced NASH. We investigated whether a combination of two active chemical components, geniposide and chlorogenic acid (GC), at a specific ratio (67 : 1), ameliorates diet-induced NASH and the underlying mechanisms involved. C57BL/6J mice exposed to a high-fat and high-cholesterol (HFHC) diet containing cholesterol, choline, and high-sugar drinking water, as well as RAW264.7 cells stimulated with lipopolysaccharide (LPS) were studied. The combination exerted a therapeutic effect on HFHC-induced NASH in mice. Simultaneously, GC was found to reduce the expression of cytokines secreted by hepatic macrophages, including tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-1β, IL-6, monocyte chemotactic protein 1 (MCP-1), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Moreover, GC reduced the number of KCs expressing F4/80. Furthermore, TNF-α, inducible nitric oxide synthase (INOS), IL-1β, and IL-6 mRNA and TNF-α protein expression levels were suppressed upon GC treatment in RAW264.7 cells. Our findings suggest that GC has a strong anti-inflammatory effect in NASH, and this effect can be attributed to the suppression of KC activity in the liver.
Highlights
With the increasing incidence of obesity, diabetes, and metabolic syndromes, nonalcoholic fatty liver disease (NAFLD) is emerging as one of the most common causes of chronic liver disease
The mice in the high-fat and high-cholesterol (HFHC) group were fed a high-trans fat, high cholesterol, and high bile salt feed combined with water containing high sugar (45% of the feed energy was derived from fat, Trophic Animal Feed High-Tech Co., Ltd, China, TP23302S, composition of sugar water: 55%fructose + 45%sucrose, concentration 42 g/L), to establish the animal model of nonalcoholic steatohepatitis (NASH) mice
The results showed that the mRNA levels of inducible nitric oxide synthase (INOS) (P < 0:01), IL-1β (P < 0:01), and IL-6 (P < 0:01) were significantly increased in the LPS group compared with the control group
Summary
With the increasing incidence of obesity, diabetes, and metabolic syndromes, nonalcoholic fatty liver disease (NAFLD) is emerging as one of the most common causes of chronic liver disease. The acronym metabolic associated fatty liver disease (MAFLD) has replaced the use of NAFLD in literature [1]. NAFLD encompasses a wide spectrum of liver damage, ranging from benign lipid accumulation in the liver (steatosis) to nonalcoholic steatohepatitis (NASH) characterized by fat vacuoles, lobular inflammation, and hepatocyte damage in the form of ballooning and apoptosis [2, 3]. The causes of progression from steatosis to NASH are lipotoxicity, oxidative stress, and inflammation [5]. Novel and effective therapies to improve the prognosis of NASH are urgently needed. The pathophysiology of NASH is multifactorial and not yet completely understood [6]; innate immunity is a major contributing factor in which liver-
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