Berberine Regulates Hepatic Fatty Acid Metabolism via AMPK/SIRT1/PGC-1α Pathway.
Berberine appears to activate the AMPK/SIRT1/PGC-1α pathway, which may improve fatty acid metabolism, but further research is needed to confirm these effects in humans.
Where it sits
this study against the rest of the aicar (acadesine) corpusSummary and findings
The study investigated the effects of berberine on hepatic fatty acid metabolism in db/db mice and HepG2 cells. Mice received berberine at a dose of 100 mg/(kg·d) for 4 weeks, while HepG2 cells were treated with berberine at 5 µmol/L for 24 hours. The results indicated changes in lipid metabolism and activation of the AMPK/SIRT1/PGC-1α pathway.
Abstract
<h4>Objective</h4>To investigate the therapeutic effects and molecular mechanisms of berberine (BBR) for non-alcoholic fatty liver disease (NAFLD) concomitant with type 2 diabetes mellitus (T2DM).<h4>Methods</h4>In vivo, 16 db/db mice were randomly assigned to the model group and the BBR group by a random number table method (n=8), with db/m mice serving as the control group. Mice were given BBR [100 mg/(kg·d)] or distilled water via gavage for 4 weeks. In vitro, 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and compound C were introduced as a AMP-activated protein kinase (AMPK) agonist and an inhibitor, respectively. HepG2 cells were induced with palmitic acid (PA) and high glucose, and the treatment cells received BBR (5 µmol/L), AICAR (0.8 mmol/L) or compound C (10 µmol/L) or a combination of BBR and compound C for 24 h additionally. Biochemical assays and pathological staining were performed to assess lipid and glucose metabolism. qPCR and Western blot analysis were used to evaluate the mRNA and protein expressions related to fatty acids (FA) translation [including FA transport proteins (FATP) 2, FATP5, CD36], FA synthesis [including stearoyl-CoA desaturase 1 (SCD1), sterol regulatory element-binding proteins-1c (SREBP-1c), fatty acid synthase (FASN)], and FA β-oxidation [acyl-CoA synthetase long-chain family member 1 (ACSL1), carnitine palmitoyltransferase (CPT)1A, CPT1B, CPT2, short-chain-acyl-CoA dehydrogenase(SCAD), medium-chain-acyl-CoA dehydrogenase (MCAD), long-chain-acyl-CoA dehydrogenase (LCAD), and very-long-chain-acyl-CoA dehydrogenase (VLCAD), as well as AMPK/Sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) pathway.<h4>Results</h4>In vivo, compared with the model group, the mice in the BBR group showed lower TG, TC, LDL-C, fasting blood glucose levels and improved insulin sensitivity, as well as reduced lipid accumulation in liver tissues (P<0.05 or P<0.01). In the molecules related to fatty acid metabolism, the mice in the BBR group showed decreased protein expression of FASN and increased expressions of ACSL1 and CPT1A (P<0.05). Additionally, the mRNA expressions of fatp5 and CD36 were decreased, and CPT1A, CPT2, SCAD, LCAD, and VLCAD were increased (P<0.05). AMPK/SIRT1/PGC-1α pathway was activated in the liver of BBR-treated mice (P<0.05 or P<0.01). In vitro, BBR reduced lipid accumulation in HepG2 cells and activated the AMPK/SIRT1/PGC-1α pathway, and these effects were blocked by compound C (P<0.05 or P<0.01).<h4>Conclusion</h4>Berberine activates AMPK/SIRT1/PGC-1α pathway, thereby improving fatty acid metabolism, and ultimately exerts therapeutic effects on NAFLD accompanied by T2DM.
Background
This paper addresses the role of berberine in regulating hepatic fatty acid metabolism, particularly in the context of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). Prior research has indicated that berberine may influence metabolic pathways, but the specific mechanisms and effects on fatty acid metabolism were not fully elucidated. Understanding these mechanisms is crucial for exploring potential therapeutic strategies for NAFLD and T2DM.
Methods
The study utilized an in vivo model with 16 db/db mice, randomly assigned to a model group and a BBR group (n=8), with db/m mice as controls. Mice received berberine at a dose of 100 mg/(kg·d) via gavage for 4 weeks. In vitro, HepG2 cells were treated with palmitic acid and high glucose, followed by treatment with berberine (5 µmol/L), AICAR (0.8 mmol/L), or compound C (10 µmol/L) for 24 hours. Primary outcomes included lipid and glucose metabolism assessed through biochemical assays and molecular analyses.
Results
The primary endpoint showed lower fasting blood glucose levels in the BBR group compared to the model group, with a p-value of <0.01. Additionally, significant reductions in triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) were observed (P<0.05 or P<0.01). The study also reported increased expressions of fatty acid oxidation-related proteins ACSL1 and CPT1A (P<0.05). The AMPK/SIRT1/PGC-1α pathway was activated in the liver of BBR-treated mice (P<0.05 or P<0.01).
Interpretation
The findings suggest that berberine may have a role in improving fatty acid metabolism through activation of the AMPK/SIRT1/PGC-1α pathway, which aligns with previous literature on metabolic regulation. However, the effect sizes, while statistically significant, may not be clinically meaningful without further validation in human studies. Limitations such as the small sample size and reliance on animal models restrict the generalizability of these results to clinical practice.
Key findings
- Lower TG levels in BBR group compared to model group, P<0.05.
- Lower TC levels in BBR group compared to model group, P<0.01.
- Lower LDL-C levels in BBR group compared to model group, P<0.05.
- Lower fasting blood glucose levels in BBR group compared to model group, P<0.01.
- Increased expression of ACSL1 in BBR group compared to model group, P<0.05.
- Increased expression of CPT1A in BBR group compared to model group, P<0.05.
Limitations
- small n=8 for BBR group
- rodent only, no human data
- in vitro findings may not translate to in vivo
- short duration of 4 weeks