Abstract
Fatty liver disease (FLD) is characterized by lipid accumulation in hepatocytes and is accompanied by secretory pathway dysfunction, resulting in induction of the unfolded protein response (UPR). Activating transcription factor 6 (ATF6), one of three main UPR sensors, functions to both promote FLD during acute stress and reduce FLD during chronic stress. There is little mechanistic understanding of how ATF6, or any other UPR factor, regulates hepatic lipid metabolism to cause disease. We addressed this using zebrafish genetics and biochemical analyses and demonstrate that Atf6 is necessary and sufficient for FLD. atf6 transcription is significantly upregulated in the liver of zebrafish with alcoholic FLD and morpholino-mediated atf6 depletion significantly reduced steatosis incidence caused by alcohol. Moreover, overexpression of active, nuclear Atf6 (nAtf6) in hepatocytes caused FLD in the absence of stress. mRNA-Seq and qPCR analyses of livers from five day old nAtf6 transgenic larvae revealed upregulation of genes promoting glyceroneogenesis and fatty acid elongation, including fatty acid synthase (fasn), and nAtf6 overexpression in both zebrafish larvae and human hepatoma cells increased the incorporation of 14C-acetate into lipids. Srebp transcription factors are key regulators of lipogenic enzymes, but reducing Srebp activation by scap morpholino injection neither prevented FLD in nAtf6 transgenics nor synergized with atf6 knockdown to reduce alcohol-induced FLD. In contrast, fasn morpholino injection reduced FLD in nAtf6 transgenic larvae and synergistically interacted with atf6 to reduce alcoholic FLD. Thus, our data demonstrate that Atf6 is required for alcoholic FLD and epistatically interacts with fasn to cause this disease, suggesting triglyceride biogenesis as the mechanism of UPR induced FLD.
Highlights
The unfolded protein response (UPR) acts in most cells to maintain homeostasis within the protein secretory pathway during physiological conditions
We identify activating transcription factor 6 (Atf6), one of three UPR sensors, as necessary and sufficient for steatosis and show that Atf6 activation can promote lipogenesis, providing a direct connection between the stress response and lipid metabolism
Fatty acid synthase is a key lipogenic enzyme and we show that fasn is required for fatty liver in response to both ethanol and Atf6 overexpression
Summary
The unfolded protein response (UPR) acts in most cells to maintain homeostasis within the protein secretory pathway during physiological conditions. Most FLD etiologies are accompanied by impairment of protein secretion by hepatocytes that result in serum protein deficiencies, which are most apparent in chronic alcoholics and contribute to the systemic complications of alcoholic liver disease (ALD). These defects are reflected in many reports demonstrating that alcohol induces some UPR sensors and targets in the liver of mice [1,8], rats [9], micropigs [10], and zebrafish [11,12,13]. It is not clear whether these genes, or other UPR effectors, contribute to steatosis
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