Continuous (chronic or sub-chronic) alcohol consumption induces a metabolic byproduct known as ketone bodies, and the accumulation of ketones leads to a life-threatening syndrome called alcoholic ketoacidosis. However, the mechanism underlining the physiological effects of ketone accumulation in alcoholic liver disease (ALD) is still in its infancy. Here, we discovered that mitochondrial acetyl-CoA accumulation was diverted into the ketogenesis pathway in ethanol-fed mice and ethanol-exposed hepatocytes. Unexpectedly, global protein lysine β-hydroxybutyrylation (Kbhb) was induced in response to increased ketogenesis-derived β-hydroxybutyrate (BHB) levels both in hepatocytes and in livers of mice. Focusing on the solute carrier family (SLCs), we found that SLC25A5 presented obvious Kbhb at lysine residues 147 and 166. Kbhb modifications at these two lysine residues stabilized SLC25A5 expression by blocking ubiquitin-proteasome pathway. Subsequent mutation analysis revealed that Kbhb of SLC25A5 at K147 and K166 had site-specific regulatory roles by increasing peroxisome proliferator activated receptor gamma (PPARγ) expression, which further promoting lipogenesis. Additionally, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 (HMGCS2), a rate-limiting enzyme for BHB production, was profoundly induced by ethanol exposure, and knockout of Hmgcs2 with CRISPR/Cas9 attenuated SLC25A5 Kbhb. Together, our study demonstrated a widespread Kbhb landscape under ethanol exposure and clarified a physiological effect of Kbhb modification on liver lipid accumulation.
Keywords: Alcoholic liver disease; Ethanol metabolism; Lipid accumulation; β-hydroxybutyrate; β-hydroxybutyrylation.
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