Berberine Alleviates Hepatic Steatosis by Restoring CPT1α Histone Acetylation and Modulating HDAC2/SIRT2.

BACKGROUND

High-fat diet (HFD)-driven hepatic steatosis is associated with impaired mitochondrial fatty acid oxidation and dysregulated expression of genes that control lipid disposal. Carnitine palmitoyltransferase 1α (CPT1α), encoded by Cpt1a, is the rate-limiting enzyme for mitochondrial fatty acid β-oxidation and responds to nutritional stress. However, the chromatin mechanisms that regulate Cpt1a in diet-induced steatosis remain incompletely defined.

OBJECTIVES

To map histone modifications at the hepatic Cpt1a locus and determine whether berberine (BBR) is associated with the restoration of Cpt1a transcription through histone acetylation remodeling.

METHODS

Male Sprague-Dawley rats were assigned to the normal diet (ND), high-fat diet (HFD), or berberine (BBR)+HFD group (n = 8 initially), with individual rats as the experimental unit. ChIP-qPCR was performed on archived liver samples (ND, n = 6; HFD, n = 8; BBR+HFD, n = 8) and normalized to input DNA. In BRL cells, TSA (100 nM) and SAHA (20 μM) were used to assess HDAC-sensitive regulation of Cpt1a.

RESULTS

HFD reduced H3/H4 acetylation and increased H3K9 methylation at Cpt1a regulatory regions. BBR restored H3/H4 acetylation, selectively reduced H3K9me3 at +12 kb, and attenuated HFD-induced increases in HDAC2 and SIRT2 mRNA (approximately 40-fold and 3.8-fold, respectively) toward baseline. TSA and SAHA increased Cpt1a mRNA at 24 h by approximately 8.1-fold and 5.4-fold, respectively. Palmitate reduced Cpt1a expression by approximately 58%, and this repression was reversed by BBR or TSA.

CONCLUSIONS

BBR alleviates HFD-induced hepatic steatosis, concomitant with the restoration of Cpt1a histone acetylation and modulation of HDAC2/SIRT2. These data support, but do not prove, an HDAC2/SIRT2-linked chromatin mechanism and should be interpreted as a candidate pathway requiring further functional validation.