Abstract
Impaired hepatic lipid metabolism is a hallmark of non-alcoholic fatty liver disease (NAFLD), which has no effective treatment option. Recently, Notch signaling has been identified as an important mediator of hepatic lipid metabolism. Lingonberry (Vaccinium vitis-idaea L.) is an anthocyanin-rich fruit with significant lipid-lowering properties. In this study, we examined how lingonberry influenced Notch signaling and fatty acid metabolism in a mouse model of NAFLD. Mice (C57BL/6J) fed a high-fat diet (HFD) for 12 weeks developed fatty liver and activated hepatic Notch1 signaling. Lingonberry supplementation inhibited hepatic Notch1 signaling and improved lipid profile by improving the expression of the genes involved in hepatic lipid metabolism. The results were verified using a palmitic-acid-challenged cell model. Similar to the animal data, palmitic acid impaired cellular lipid metabolism and induced Notch1 in HepG2 cells. Lingonberry extract or cyanidin-3-glucoside attenuated Notch1 signaling and decreased intracellular triglyceride accumulation. The inhibition of Notch in the hepatocytes attenuated sterol-regulatory-element-binding-transcription-factor-1 (SREBP-1c)-mediated lipogenesis and increased the expression of carnitine palmitoyltransferase-I-alpha (CPTIα) and acyl-CoA oxidase1 (ACOX1). Taken together, lingonberry’s hepatoprotective effect is mediated by, in part, improving hepatic lipid metabolism via inhibiting Notch1 signaling in HFD-induced fatty liver.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world [1]
Another study reported that Notch receptor 1 (Notch1) deficiency increased fatty acid oxidation in the liver by elevating the expression of fatty acid oxidation genes [39]. In accordance with these findings, our results suggest that lingonberry extract or C3Glu reduced cellular lipid accumulation by decreasing lipogenesis and increasing fatty acid oxidation, in part through inhibiting Notch1 signaling
high-fat diet (HFD) feeding did not change the expression of acyl-CoA oxidase1 (ACOX1) and CPTIα, lingonberry supplementation significantly increased the expression of these two genes in the liver. These results suggest that dietary supplementation of lingonberry attenuated HFD-induced hepatic lipid accumulation by inhibiting de novo lipid synthesis and improving fatty acid oxidation in the liver
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world [1]. NAFLD is defined by accumulating lipids (mainly triglyceride) comprising more than 5% of the liver weight [2]. NAFLD comprises a broad pathological spectrum ranging from simple fatty liver (steatosis) to fatty liver with hepatic inflammation (steatohepatitis), fibrosis and cirrhosis [3]. Elevated hepatic lipid influx, impaired lipid metabolism and decreased lipid export from the liver are the primary causes of fatty liver [3]. Chronic lipid accumulation in the liver triggers oxidative stress and inflammation, the driving forces of progressing steatosis to nonalcoholic steatohepatitis (NASH). Impaired hepatic lipid metabolism is common in NAFLD patients and in high-fat-diet (HFD)-fed rodent models [4]. It has been demonstrated that hepatic de novo lipogenesis is three-fold higher in human NAFLD subjects than in control subjects [5]. Elevated fatty acid synthesis attenuates lipolysis/fatty acid oxidation by inhibiting fatty acid transportation into the mitochondrial
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