Berberine Ameliorates Hepatic Steatosis and Suppresses Liver and Adipose Tissue Inflammation in Mice with Diet-induced Obesity

Abstract

Increasing evidence demonstrates that berberine (BBR) is beneficial for obesity-associated non-alcoholic fatty liver disease (NAFLD). However, it remains to be elucidated how BBR improves aspects of NAFLD. Here we revealed an AMP-activated protein kinase (AMPK)-independent mechanism for BBR to suppress obesity-associated inflammation and improve hepatic steatosis. In C57BL/6J mice fed a high-fat diet (HFD), treatment with BBR decreased inflammation in both the liver and adipose tissue as indicated by reduction of the phosphorylation state of JNK1 and the mRNA levels of proinflammatory cytokines. BBR treatment also decreased hepatic steatosis, as well as the expression of acetyl-CoA carboxylase and fatty acid synthase. Interestingly, treatment with BBR did not significantly alter the phosphorylation state of AMPK in both the liver and adipose tissue of HFD-fed mice. Consistently, BBR treatment significantly decreased the phosphorylation state of JNK1 in both hepatoma H4IIE cells and mouse primary hepatocytes in both dose-dependent and time-dependent manners, which was independent of AMPK phosphorylation. BBR treatment also caused a decrease in palmitate-induced fat deposition in primary mouse hepatocytes. Taken together, these results suggest that BBR actions on improving aspects of NAFLD are largely attributable to BBR suppression of inflammation, which is independent of AMPK.

Disruption of adenosine 2A receptor exacerbates NAFLD through increasing inflammatory responses and SREBP1c activity

“…A). We examined the pathophysiological relevance of hepatic expression of A 2A R in C57BL/6J mice, which display obesity‐associated NAFLD upon feeding HFD . HFD‐fed C57BL/6J mice displayed a significant increase in liver A 2A R messenger RNAs (mRNAs) compared with LFD‐fed mice (Fig.…”

“…Numerous studies of both human subjects and rodent models demonstrate that obesity significantly increases the incidence of NAFLD . Accordingly, obesity‐associated inflammation is accepted as a critical factor that initiates or exacerbates NAFLD.…”

Nutritional approaches for managing obesity-associated metabolic diseases

“…However, more imperative to health and metabolism is the well-documented association between long-term HFD and the generation of inflammation. For example, it is well established that feeding a saturated fatty acid-enriched HFD to mice causes inflammation in various tissues and organs including adipose tissue (Huo, et al 2010; Xu, et al 2003), the liver (Cai, et al 2005; Guo, et al 2016; Woo, et al 2014), small intestine (Botchlett, et al 2016; Guo, et al 2013), and even the brain (Tang, et al 2015; Zhang, et al 2008). Significantly, chronic HFD-induced inflammation is now considered as a major factor in the onset of many metabolic disorders including obesity, T2DM, cardiovascular disease and some forms of cancer (Egger 2012; Hotamisligil 2006; Terzić, et al).…”

“…It seems multiple mechanisms exist for how overnutrition stimulates this process. For example, many studies have reported increased expressions of genes involved in fat deposition and/or decreased expressions of genes that regulate beta oxidation following overnutrition (Guo et al 2016; Hudgins, et al 2000). Overnutrition with an HFD is a particularly common cause of weight gain/obesity as it is shown to contribute to both subcutaneous and visceral WAT deposition (Kubant, et al 2015).…”

“…HFD can also directly impair lipid metabolism. Specifically, it leads to reduced lipolysis through inhibition of 5′ AMP-activated protein kinase (Barroso, et al 2011) and increased lipid accumulation via increased expression of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) (Guo et al 2016), all of which can intensify systemic insulin resistance.…”