Abstract
Adipose tissue lipolysis produces glycerol and nonesterified fatty acids (NEFA) that serve as energy sources during nutrient scarcity. Adipose tissue lipolysis is tightly regulated and excessive lipolysis causes hepatic steatosis, as NEFA released from adipose tissue constitutes a major source of TG in the liver of patients with nonalcoholic fatty liver diseases. Here we show that the liver-enriched transcription factor CREBH is activated by TG accumulation and induces FGF21, which suppresses adipose tissue lipolysis, ameliorating hepatic steatosis. CREBH-deficient mice developed severe hepatic steatosis due to increased adipose tissue lipolysis, when fasted or fed a high-fat low-carbohydrate ketogenic diet. FGF21 production was impaired in CREBH-deficient mice, and adenoviral overexpression of FGF21 suppressed adipose tissue lipolysis and improved hepatic steatosis in these mice. Thus, our results uncover a negative feedback loop in which CREBH regulates NEFA flux from adipose tissue to the liver via FGF21.
Highlights
Cyclic AMP-responsive element-binding protein H (CREBH, encoded by Creb3l3) is a bZiP transcription factor that is highly expressed in the liver[17,18]
Coupled with our previous finding that CREBH is activated in fatty livers[23], we propose that CREBH plays a central role in hepatic TG homeostasis by inducing FGF21, which suppresses NEFA flux to the liver, thereby ameliorating hepatic steatosis
We demonstrate that CREBH is activated by TG accumulation in the liver and induces FGF21, which suppresses lipolysis in adipose tissue, thereby limiting NEFA flow to the liver (Fig. 7)
Summary
Cyclic AMP-responsive element-binding protein H (CREBH, encoded by Creb3l3) is a bZiP transcription factor that is highly expressed in the liver[17,18]. Zhang and colleagues demonstrated that a group of genes involved in de novo lipogenesis, fatty acid elongation, fatty acid oxidation were down-regulated in the liver of CREBH deficient mice fed the Paigen diet compared to WT controls[24]. It was unexplored whether this gene expression change impacts TG accumulation in CREBH deficient liver, or reflects the consequence of severe steatosis in these mice. We demonstrate that CREBH-deficient mice develop severe hepatic steatosis, when fasted or fed a high-fat low-carbohydrate ketogenic diet (KD), conditions in which fatty acids serve as major energy source. Coupled with our previous finding that CREBH is activated in fatty livers[23], we propose that CREBH plays a central role in hepatic TG homeostasis by inducing FGF21, which suppresses NEFA flux to the liver, thereby ameliorating hepatic steatosis
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