Berberine Regulates Hepatic Fatty Acid Metabolism via AMPK/SIRT1/PGC-1α Pathway

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).

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.

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).

Berberine activates AMPK/SIRT1/PGC-1α pathway, thereby improving fatty acid metabolism, and ultimately exerts therapeutic effects on NAFLD accompanied by T2DM.