Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis

Hegardt, Fausto G.

doi:10.1042/bj3380569

Cited by 294 publications

(242 citation statements)

References 158 publications

(183 reference statements)

Supporting

Mentioning

230

Contrasting

Unclassified

Order By: Relevance

“…βHB synthesis is dependent on the activity of mitochondrial HMGCS2. 25 To Figure 1 βHB increases differentiation in Caco-2 cells. (a) Caco-2 cells were treated with βHB (10 mM) for 48 h. Total RNA was extracted, and SI, KRT20, p21 Waf1 and CDX2 mRNA expression was assessed by real-time RT-PCR.…”

Section: Resultsmentioning

confidence: 99%

Ketogenesis contributes to intestinal cell differentiation

et al. 2016

View full text Add to dashboard Cite

The intestinal epithelium undergoes a continual process of proliferation, differentiation and apoptosis. Previously, we have shown that the PI3K/Akt/mTOR pathway has a critical role in intestinal homeostasis. However, the downstream targets mediating the effects of mTOR in intestinal cells are not known. Here, we show that the ketone body β-hydroxybutyrate (βHB), an endogenous inhibitor of histone deacetylases (HDACs) induces intestinal cell differentiation as noted by the increased expression of differentiation markers (Mucin2 (MUC2), lysozyme, IAP, sucrase-isomaltase, KRT20, villin, Caudal-related homeobox transcription factor 2 (CDX2) and p21 Waf1 ). Conversely, knockdown of the ketogenic mitochondrial enzyme hydroxymethylglutaryl CoA synthase 2 (HMGCS2) attenuated spontaneous differentiation in the human colon cancer cell line Caco-2. Overexpression of HMGCS2, which we found is localized specifically in the more differentiated portions of the intestinal mucosa, increased the expression of CDX2, thus further suggesting the contributory role of HMGCS2 in intestinal differentiation. In addition, mice fed a ketogenic diet demonstrated increased differentiation of intestinal cells as noted by an increase in the enterocyte, goblet and Paneth cell lineages. Moreover, we showed that either knockdown of mTOR or inhibition of mTORC1 with rapamycin increases the expression of HMGCS2 in intestinal cells in vitro and in vivo, suggesting a possible cross-talk between mTOR and HMGCS2/βHB signaling in intestinal cells. In contrast, treatment of intestinal cells with βHB or feeding mice with a ketogenic diet inhibits mTOR signaling in intestinal cells. Together, we provide evidence showing that HMGCS2/βHB contributes to intestinal cell differentiation. Our results suggest that mTOR acts cooperatively with HMGCS2/βHB to maintain intestinal homeostasis.

show abstract

Section: Resultsmentioning

confidence: 99%

Ketogenesis contributes to intestinal cell differentiation

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Hepatic Fgf21 mRNA concentrations were at the lower limits of detection by qRT-PCR in the livers of both fed and fasting CONV-D and GF Ppar␣Ϫ/Ϫ animals, emphasizing the dependence of this gene's expression on Ppar␣. The mitochondrial form of 3-hydroxy-3-methylglutarylCoA synthase (Hmgcs2) is a critical ketogenic enzyme in the liver and a Ppar␣ target (20). Hmgcs2 expression was unchanged by fasting in GF mice, but was induced 1.96 Ϯ 0.09-fold in CONV-D animals (P Ͻ 0.05) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulation of myocardial ketone body metabolism by the gut microbiota during nutrient deprivation

Crawford

Crowley

Sambandam

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

230

203

View full text Add to dashboard Cite

Studies in mice indicate that the gut microbiota promotes energy harvest and storage from components of the diet when these components are plentiful. Here we examine how the microbiota shapes host metabolic and physiologic adaptations to periods of nutrient deprivation. Germ-free (GF) mice and mice who had received a gut microbiota transplant from conventionally raised donors were compared in the fed and fasted states by using functional genomic, biochemical, and physiologic assays. A 24-h fast produces a marked change in gut microbial ecology. Shortchain fatty acids generated from microbial fermentation of available glycans are maintained at higher levels compared with GF controls. During fasting, a microbiota-dependent, Ppar␣-regulated increase in hepatic ketogenesis occurs, and myocardial metabolism is directed to ketone body utilization. Analyses of heart rate, hydraulic work, and output, mitochondrial morphology, number, and respiration, plus ketone body, fatty acid, and glucose oxidation in isolated perfused working hearts from GF and colonized animals (combined with in vivo assessments of myocardial physiology) revealed that the fasted GF heart is able to sustain its performance by increasing glucose utilization, but heart weight, measured echocardiographically or as wet mass and normalized to tibial length or lean body weight, is significantly reduced in both fasted and fed mice. This myocardial-mass phenotype is completely reversed in GF mice by consumption of a ketogenic diet. Together, these results illustrate benefits provided by the gut microbiota during periods of nutrient deprivation, and emphasize the importance of further exploring the relationship between gut microbes and cardiovascular health. energy homeostasis ͉ gnotobiotic mice ͉ gut-heart metabolic axis ͉ host-microbial mutualism ͉ isolated perfused working heart

show abstract

“…We hypothesized that PksG catalyzed the transfer of OCH 2 COO Ϫ from Ac-S-AcpK to a ␤-ketothioester polyketide intermediate linked to one of the consecutive thiolation domains of PksL, in a reaction analogous to that catalyzed by HMG-CoA synthase (22,23). We chose acetoacetyl (Acac)-S-PksL-T2 as a model substrate for this reaction.…”

Section: Resultsmentioning

confidence: 99%

Convergence of isoprene and polyketide biosynthetic machinery: Isoprenyl- S -carrier proteins in the pksX pathway of Bacillus subtilis

Calderone

Kowtoniuk

Kelleher

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

174

230

View full text Add to dashboard Cite

The pksX gene cluster from Bacillus subtilis is predicted to encode the biosynthesis of an as yet uncharacterized hybrid nonribosomal peptide͞polyketide secondary metabolite. We used a combination of biochemical and mass spectrometric techniques to assign functional roles to the proteins AcpK, PksC, PksL, PksF, PksG, PksH, and PksI, and we conclude that they act to incorporate an acetate-derived ␤-methyl branch on an acetoacetyl-S-carrier protein and ultimately generate a ⌬ 2 -isoprenyl-S-carrier protein. This work highlights the power of mass spectrometry to elucidate the functions of orphan biosynthetic enzymes, and it details a mechanism by which single-carbon ␤-branches can be inserted into polyketide-like structures. This pathway represents a noncanonical route to the construction of prenyl units and serves as a prototype for the intersection of isoprenoid and polyketide biosynthetic manifolds in other natural product biosynthetic pathways.mass spectrometry ͉ orphan gene cluster ͉ hybrid nonribosomal peptide͞polyketide ͉ polyketide methylation P olyketides and nonribosomal peptides are classes of secondary metabolites that are synthesized by the iterative coupling of malonyl (Mal) derivatives and amino acids, respectively. The catalytic machinery responsible for the biosynthesis of these natural products comprises modular synthases that incorporate, and often subsequently tailor, monomer units into the growing small molecule by a thiotemplated mechanism. Often, the sequence of protein domains and modules is colinear with respect to the sequence of biosynthetic reactions catalyzed by the polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) machinery (1-3). Because of their highly modular nature, the small-molecule products of PKSs, NRPSs, and hybrid NRPS-PKS systems can often be predicted by bioinformatic approaches, and there have been recent experimental validations of such predictions (4-6). However, for many cases in which the biosynthetic product encoded by a given gene cluster is unknown, functional characterization of the synthase by bioinformatic methods alone is difficult or impossible.One such orphan cluster for which the product structure is unknown is the hybrid NRPS-PKS pksX cluster from Bacillus subtilis (7-9). Although the pksX cluster has been proposed to encode the biosynthesis of difficidin (7,9,10), recent work has demonstrated that the NRPS portion of the gene cluster is active, disqualifying difficidin, which does not contain any amines, as a candidate for the biosynthetic product of this cluster (11). Long thought to be cryptic, there is now evidence that it is responsible for the biosynthesis of a product that kills streptomycetes (P. D. Straight, M. A. Fischbach, C.T.W., and R. Kolter, unpublished results). Additionally, this cluster does not follow the usual NRPS-PKS colinearity rules because it has only three trans-acting acyltransferases that may load up to 17 of the 20 predicted thiolation domains of the cluster.We were intrigued by a series of predicted ORFs withi...

show abstract

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis

Cited by 294 publications

References 158 publications

Ketogenesis contributes to intestinal cell differentiation

Ketogenesis contributes to intestinal cell differentiation

Regulation of myocardial ketone body metabolism by the gut microbiota during nutrient deprivation

Convergence of isoprene and polyketide biosynthetic machinery: Isoprenyl- S -carrier proteins in the pksX pathway of Bacillus subtilis

Contact Info

Product

Resources

About