Berberine attenuates nonalcoholic hepatic steatosis through the AMPK-SREBP-1c-SCD1 pathway

Jun 22, 2019Free radical biology & medicine

Berberine reduces fatty liver by affecting energy and fat-making pathways

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Abstract

Berberine (BBR) significantly reduces triglyceride levels in the liver of mice fed a high-fat diet.

Increased expression of stearyl-coenzyme A desaturase 1 (SCD1) was observed in the liver of NAFLD patients and ob/ob mice.
BBR decreased hepatic triglyceride accumulation and lowered the expression of SCD1 and related genes in both animal and cell models.
Knockdown of SCD1 expression replicated BBR's effect by reducing triglyceride levels in fatty liver cells.
Overexpression of SCD1 counteracted the triglyceride-lowering effect of BBR.
BBR enhanced the phosphorylation of AMPK and SREBP-1c, indicating activation of the AMPK-SREBP-1c pathway.
The suppression of SCD1 by BBR is linked to the activation of specific regulatory elements in the SCD1 promoter.

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BACKGROUND: Berberine (BBR), a natural compound extracted from Chinese herb, has been shown to effectively attenuate nonalcoholic fatty liver disease (NAFLD) in clinic. However, the mechanism underlying the effect of BBR is not fully understood. Stearyl-coenzyme A desaturase 1 (SCD1) mediates lipid metabolism in liver. Therefore, we hypothesized that SCD1 mediated the beneficial effect of BBR on NAFLD.

METHODS: The expression of SCD1 was measured in the liver of NAFLD patients and ob/ob mice. The effect of BBR on NAFLD was evaluated in C57BL/6 J mice on high fat diet (HFD). The effect of BBR was also investigated in HepG2 and AML12 cells exposed to high glucose and palmitic acid. Oil red O staining was performed to detect triglyceride (TG) level. Quantitative real-time polymerase chain reaction and Western blot were used to detect the messenger ribonucleic acid (mRNA) and protein expression of target genes. The activity of SCD1 promoter was measured by dual-luciferase reporter assay.

RESULTS: The expression of SCD1 was increased in the liver of NAFLD patients and ob/ob mice. BBR reduced hepatic TG accumulation and decreased the expressions of hepatic SCD1 and other TG synthesis related genes both in vivo and in vitro. Knockdown of SCD1 expression mimicked the effect of BBR decreasing TG level in steatotic hepatocytes, whereas overexpression of SCD1 attenuated the effect of BBR. Mechanistically, BBR promoted the phosphorylation of AMP-activated protein kinase (AMPK) and sterol regulatory element-binding protein-1c (SREBP-1c) in HepG2 cells and the liver of HFD-fed mice. Activation of the AMPK-SREBP-1c pathway and sterol regulatory element (SRE) motif in SCD1 promoter (-920/-550) was responsible for the BBR-induced suppression of SCD1.

CONCLUSION: BBR reduces liver TG synthesis and attenuates hepatic steatosis through the activation of AMPK-SREBP-1c-SCD1 pathway.

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Berberine attenuates nonalcoholic hepatic steatosis through the AMPK-SREBP-1c-SCD1 pathway

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