Deng Changping,Shi Min,Fu Rong,Zhang Yi,Wang Qiang,Zhou Yang,Wang Yao,Ma Xingyuan,Kai Guoyin
Phenolic acids and tanshinones are major bioactive ingredients in Salvia miltiorrhiza, which possess pharmacological activities with great market demand. However, transcriptional regulation of phenolic acid and tanshinone biosynthesis remains poorly understood. Here, a basic leucine zipper transcription factor (TF) named SmbZIP1 was screened from the abscisic acid (ABA)-induced transcriptome library. Overexpression of SmbZIP1 positively promoted phenolic acid biosynthesis by enhancing expression of biosynthetic genes such as cinnamate-4-hydroxylase (C4H1). Furthermore, biochemical experiments revealed that SmbZIP1 bound the G-Box-like1 element in the promoter of the C4H1 gene. Meanwhile, SmbZIP1 inhibited accumulation of tanshinones mainly by suppressing the expression of biosynthetic genes including geranylgeranyl diphosphate synthase (GGPPS) which was confirmed as a target gene by in vitro and in vivo experiments. In contrast, the phenolic acid content was reduced and tanshinone was enhanced in CRISPR/Cas9 [clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9]-mediated knockout lines. In addition, the previously reported positive regulator of tanshinone biosynthesis, SmERF1L1, was found to be inhibited in SmbZIP1 overexpression lines indicated by RNA sequencing, and was proven to be the target of SmbZIP1. In summary, this work uncovers a novel regulator and deepens our understanding of the transcriptional and regulatory mechanisms of phenolic acid and tanshinone biosynthesis, and also sheds new light on metabolic engineering in S. miltiorrhiza.
Organisms adapt to fasting by remodeling energy metabolism across tissues. We identify geranylgeranyl pyrophosphate synthase (GGPPS) in white adipose tissue (WAT) as a fasting-responsive regulator that orchestrates lipolysis and branched-chain amino acid (BCAA) metabolism. In mice, fasting downregulates GGPPS, destabilizing the BCAA-catabolizing enzyme BCAT2 via enhanced ubiquitination. Mechanistically, GGPPS scaffolds the deubiquitinase OTUB1 and BCAT2 to stabilize BCAT2, promoting BCAA catabolism. Elevated BCAAs activate adipocyte lipolysis and enhance hepatic fatty acid oxidation. Adipose-specific deletion of Ggpps phenocopies fasting responses, including enhanced lipolysis and systemic BCAA elevation. Conversely, BCAA supplementation promotes adipose lipolysis, protects against diet-induced obesity, and facilitates hepatic oxidative adaptation. In fasting mice, BCAA supplementation enhanced weight loss efficiency and prevented aberrant hepatic lipid accumulation. These findings identify GGPPS as a potential central node linking amino acid and lipid metabolism during early fasting within a multi-organ metabolic circuit.
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