Caffeine ameliorates high energy diet-induced hepatic steatosis: sirtuin 3 acts as a bridge in the lipid metabolism pathway

Abstract

The beneficial effect of caffeine-containing food on non-alcoholic fatty liver disease (NAFLD) has been widely reported. The aim of this study was to explore the effect of caffeine on hepatic steatosis. C57BL/6 mice were randomly assigned to a normal diet or a high energy diet (HED). Caffeine was given to HED mice by oral gavage. Body weights, lipids in the liver and liver damage were measured. Meanwhile, cAMP, SIRT3 or AMPK inhibitors were treated respectively before incubation with caffeine in oleate-treated HepG2 cells. SIRT3 was further silenced by siRNA to confirm the results. Caffeine significantly decreased the mass of fat tissues, lipids, ALT and AST levels in the liver of HED-treated mice. Caffeine increased the transformation of ADP to ATP and activated the cAMP/CREB/SIRT3/AMPK/ACC pathway in the liver. Nile red staining demonstrated that suppression of cAMP, SIRT3 or AMPK in oleate-treated HepG2 cells counteracted the effect of caffeine. Moreover, knocking down SIRT3 could down-regulate AMPK and ACC phosphorylation by caffeine. These results demonstrate that caffeine could improve HED-induced hepatic steatosis by promoting lipid metabolism via the cAMP/CREB/SIRT3/AMPK/ACC pathway. SIRT3 functioned as a molecular bridge connecting caffeine and lipid metabolism.

Effects and mechanisms of caffeine to improve immunological and metabolic abnormalities in diet-induced obese rats

“…Administration of a chronic PPAR␣ agonist to HFD-fed animals results in a significant reduction in visceral fat weight, whole body adiposity, and hepatic/intramuscular steatosis (19,50). It has been reported that chronic caffeine treatment reduces body fat mass and adiposity in HFD-fed obese rats by activation of lipolysis (26,33,52). Accordingly, it is reasonable to observe that a decreased serum FFA level is associated with the upregulation of tissue lipolytic PPAR␣ expression in our HFDfed obese rats receiving chronic caffeine treatment.…”

“…The benefits of caffeine in relation to the immune abnormalities of obese animals and humans include the downregulation of the expression levels of TNF␣, IL-6, and MCP-1 in adipose tissue and the suppression of hepatic inflammation (9,47,52). Furthermore, the metabolic benefits of caffeine include the downregulation of hepatic lipogenic genes, the inhibition of hepatic steatosis, the improvement of hyperlipidemia, a decrease in fat mass, and an increase in systemic/hepatic insulin sensitivity; these changes have been reported in both obese animals and humans (26,30,51).…”

Celastrol exerts anti‐inflammatory effect in liver fibrosis via activation of AMPK‐SIRT3 signalling

“…Intriguingly, previous studies showed that SIRT3 could activate AMPK in some disease models. Zhang et al reported that caffeine improved hepatic steatosis partly by activation of SIRT3/AMPK pathway, and SIRT3 silencing decreased the AMPK phosphorylation in the liver . Another study indicated that SIRT3 could reduce lipid accumulation through AMPK activation in human hepatic cells, and further proved that the activity of SIRT3 deacetylase was required for SIRT3 to activate AMPK .…”

Berberine alleviates nonalcoholic fatty liver induced by a high‐fat diet in mice by activating SIRT3

“…Recently, it was reported that SIRT3 participates in the pathogenesis of NAFLD. In liver tissue from HFD-fed animal models and patients, the expression and enzymatic activity of SIRT3 are down-regulated, which alters the acetylation level of its substrates and subsequently the function in mitochondria (27)(28)(29)(30). Under normal conditions, SIRT3 knockout (KO) mice do not exhibit metabolic characteristics different from wild-type (WT) littermates (31).…”