Coffeeberry Activates the CaMKII/CREB/BDNF Pathway, Normalizes Autophagy and Apoptosis Signaling in Nonalcoholic Fatty Liver Rodent Model.

Meng-Chun Lu,Yin-Ching Chan,Mei-Due Yang,I-Te Lee,Ling-Zong Hong,Eyal Ben-Arie,Pei-Yu Kao,Wei-Ting Lin,Yu-Hsuan Lin

doi:10.3390/nu13103652

Abstract

Nonalcoholic fatty liver disease (NAFLD) shows extensive liver cell destruction with lipid accumulation, which is frequently accompanied by metabolic comorbidities and increases mortality. This study aimed to investigate the effects of coffeeberry (CB) on regulating the redox status, the CaMKII/CREB/BDNF pathway, autophagy, and apoptosis signaling by a NAFLD rodent model senescence-accelerated mice prone 8 (SAMP8). Three-month-old male SAMP8 mice were divided into a control group and three CB groups (50, 100, and 200 mg/kg BW), and fed for 12 weeks. The results show that CB reduced hepatic malondialdehyde and carbonyl protein levels. CB significantly enhanced Ca2+/calmodulin-dependent protein kinase II (CaMKII) and brain-derived neurotrophic factor (BDNF) and reduced the phospho-cAMP response element-binding protein (p-CREB)/CREB ratio. In addition, CB increased the silent information regulator T1 level, promoted Beclin 1 and microtubule-associated protein light chain 3 II expressions, and reduced phosphorylated mammalian target of rapamycin and its downstream p-p70s6k levels. CB also inhibited the expressions of apoptosis-related factors poly (ADP-ribose) polymerase-1 and the apoptosis-inducing factor. In conclusion, CB might protect the liver by reducing oxidative stress, activating the CaMKII/CREB/BDNF pathway, and improving autophagic and apoptotic expressions in a dose-dependent manner.

Highlights

With the modern western diet and the lack of exercise, nonalcoholic fatty liver disease (NAFLD) and its complications have increased worldwide, including in Asia and Taiwan.According to the Ministry of Health and Welfare report of Taiwan, chronic liver disease and liver cirrhosis were the tenth leading cause of death in 2020 [1]
BW CB group had significantly decreased carbonyl protein levels (Figure 1B). These results reveal that CB could reduce oxidative stress in the Nonalcoholic fatty liver disease (NAFLD) animal model
The present study further demonstrated that CB reduced the hepatic oxidative stress, enhanced ther demonstrated that CB reduced the hepatic oxidative stress, enhanced calmodulin-dependent protein kinase II (CaMKII)/CREB/

Summary

Introduction

With the modern western diet and the lack of exercise, nonalcoholic fatty liver disease (NAFLD) and its complications have increased worldwide, including in Asia and Taiwan.According to the Ministry of Health and Welfare report of Taiwan, chronic liver disease and liver cirrhosis were the tenth leading cause of death in 2020 [1]. BDNF has been proven to improve fatty liver and pancreatic dysfunction in type 2 diabetic mice [5]. Chronic stress, such as inflammation, affects calcium/calmodulin-protein kinase II (CaMK II), CREB, and BDNF expression, and induces the dysfunction of calcium-ion regulation [6]. The inflammatory factors, such as iNOS, COX-2, TNF-α, and IL-1 β, are reduced by inhibiting p-CREB expression [7]. The CaMKII/CREB/BDNF pathway may play a role in lessening the inflammatory response and retarding the accumulation of fat in the liver

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