Genistein Modulated Lipid Metabolism, Hepatic PPARγ, and Adiponectin Expression in Bilateral Ovariectomized Rats with Nonalcoholic Steatohepatitis (NASH)

Abstract

The aim of this study was to evaluate the protective effects of genistein on lipid accumulation and apoptosis in estrogen deficient rats with NASH. Female Sprague–Dawley rats (n = 48) were divided into ovariectomized (OVX) and non-OVX groups. Each group was then sub-divided into 3 subgroups; control, NASH (rats fed with a high-fat, high-fructose (HFHF) diet), and NASH+Gen (rats fed with HFHF diet plus daily genistein at 16 mg/kg BW). Results showed that HFHF diet induced liver fat accumulation in both non-OVX and OVX rats, which was evidenced by hepatic steatosis on liver pathology and increased hepatic free fatty acid (FFA) and triglyceride levels. Hepatic fat accumulation was significantly more severe in NASH rats with OVX than non-OVX. Hepatocyte apoptosis was more severe in NASH groups compared with that in control groups. Genistein administration significantly improved histopathology of NASH in both non-OVX and OVX rats and attenuated hepatic lipid accumulation, oxidative stress, and hepatocyte apoptosis. Genistein also down-regulated PPARγ and up-regulated adiponectin expression. In summary, NASH could be worsened by estrogen deficiency, indicating the protective action of estrogen on NASH. Genistein administration alleviated hepatic steatosis and apoptosis through the down-regulation of PPARγ and up-regulation of adiponectin expression.

Natural Polyphenols in Metabolic Syndrome: Protective Mechanisms and Clinical Applications

“…On the other hand, adiponectin is the most common adipokine known to be inversely associated with insulin resistance, lipid accumulation, inflammation, and NAFLD development [ 256 ]. Our study supports the point that most polyphenols can regulate serum adiponectin levels and adiponectin signal transduction, thereby effectively improving the inflammatory response and preventing the progression of NAFLD in animal [ 86 , 94 , 104 , 110 , 121 , 158 , 163 , 167 , 196 ]. Of note, polyphenols exhibited great beneficial effects in cell and animal models, and clinical trials are not satisfactory.…”

“…Choi and his colleagues showed that genistein also significantly inhibited lipid droplet formation in 3T3-L1 pre-adipocytes in a dose-dependent manner by reducing the expression of adipocyte-specific proteins such as PPARγ, C/EBPα, and fatty acid binding protein 4 (FABP4) and the lipogenic enzymes ATP citrate lyase (ACL), ACACA, and FASN [ 109 ]. In addition, a similar phenomenon was happened in NASH rats [ 110 ]. Genistein administration alleviated hepatic steatosis and apoptosis by downregulating PPARγ and upregulating adiponectin expression [ 110 ].…”

“…In addition, a similar phenomenon was happened in NASH rats [ 110 ]. Genistein administration alleviated hepatic steatosis and apoptosis by downregulating PPARγ and upregulating adiponectin expression [ 110 ]. Gan et al even showed that genistein promoted lipolysis in adipose tissue through miR-222, which targets an adipocyte proliferation-related gene BTG anti-proliferation factor 2 (BTG2) and a lipolytic gene adiponectin receptor 1 (ADIPOR1) [ 111 ].…”

Genistein—Opportunities Related to an Interesting Molecule of Natural Origin

“…It is possible to suggest that this effect is associated with decreased MMP-12, IL-13 and HDAC3 protein expression. Analogous observation in relation to the protective role of genistein in NASH was produced in a previous study which was also performed on estrogen deficient rats with NASH [ 118 ]. Genistein (in the same dose of 16 mg/kg body weight, dissolved in 1 mL of 0.1% DMSO, given daily by oral gavage in an eight-week experiment) improved the histopathology results, reduced the MDA levels in ovariectomized rats with NASH, decreased the accumulation of hepatic fat and attenuated hepatocyte apoptosis.…”

“…The effect of genistein on the transcription factor involved in the catabolism (PPARα) and anabolism (SREBP-1c) of lipids was studied by Seidemann et al [ 117 ]. After the incubation of primary human hepatocytes (PHHs) with free fatty acids and genistein, it was shown that the isoflavone in the concentration of 10 µM decreased the SREBP-1c protein expression in steatotic PHHs and exhibited agonistic activity in relation to PPARα in control PHHs; notwithstanding, this observation is inconsistent with results obtained by Pummoung et al [ 118 ], and the role of PPARα in NAFLD is not fully elucidated.…”