Palmitoylation of ketogenic enzyme HMGCS2 enhances its interaction with PPARα and transcription at theHmgcs2PPRE

Abstract

Excessive liver production of ketone bodies is one of many metabolic complications that can arise from diabetes, and in severe untreated cases, it can result in ketoacidosis, coma, and death. Mitochondrial HMG-CoA synthase (HMGCS2), the rate-limiting enzyme in ketogenesis, has been shown to interact with PPARalpha and act as a coactivator to up-regulate transcription from the PPRE of its own gene. Although protein palmitoylation is typically a cytosolic process that promotes membrane association, we recently identified 21 palmitoylated proteins in rat liver mitochondria, including HMGCS2. Herein, our data support a mechanism whereby palmitate is first added onto HMGCS2 active site Cys166 and then transacylated to Cys305. Palmitoylation promotes the HMGCS2/PPARalpha interaction, resulting in transcriptional activation from the Hmgcs2 PPRE. These results, together with the fact that 8 of the 21 palmitoylated mitochondrial proteins that we previously identified have nuclear receptor interacting motifs, demonstrate a novel--and perhaps ubiquitous--role for palmitoylation as a modulator of transcription.

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

“…This spillover pathway converts β-oxidation-derived acetyl-CoA, produced in excess of the hepatocyte's own energy needs, into ketone body intermediates, thus diverting carbon away from the hepatic TCA cycle and providing extrahepatic tissues with a readily oxidized fuel source. This paradigm forms an "altruistic" model of ketone body metabolism, in which the hepatocyte shares "precatabolized" energy obtained from fatty tor of fatty acid oxidation, peroxisome proliferator-activated receptor α (PPARα) (60,61). In at least 1 immortalized hepatoma cell line, HMGCS2 expression was required for fatty acid oxidation (62).…”

Investigation of Elevated Ketone Bodies in Low Carbohydrate Diet (LCD)

“…During the starvation, decreased insulin levels would easily make acyl-CoA enter the mitochondria, resulting much acetyl-CoA that is diverted into the synthesis of ketone bodies [25]. As to ketogenic pathway, mitochondrial 3-OH-3-methyglutaryl-CoA synthase and HMGCS2 are involved as rate limiting enzyme [26,27].…”

Human HMGCS2 Regulates Mitochondrial Fatty Acid Oxidation and FGF21 Expression in HepG2 Cell Line

“…It has been proposed that HMGCS2 interacts with PPAR␣ and acts as a co-activator to up-regulate transcription from the PPRE of its own gene (11,12). The HMGCS2-PPAR␣ interaction is enhanced by HMGCS2 palmitoylation (12), underlying a putative mechanism by which PPAR␣ is activated by one of its target gene products when fatty acids are available.…”

“…The HMGCS2-PPAR␣ interaction is enhanced by HMGCS2 palmitoylation (12), underlying a putative mechanism by which PPAR␣ is activated by one of its target gene products when fatty acids are available. However, this is a specific mechanism for HMGCS2, because other PPAR␣ target genes are not co-activated by HMGCS2 expression (11).…”