ArticleJCI insight2018
Hepatic ketogenic insufficiency reprograms hepatic glycogen metabolism and the lipidome.
Article in JCI insight, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
60 citing papers in PubMed, 1 synthesis or guideline pooled it, 92 citations in OpenAlex.
- Therapeutic Fasting in Reducing Chemotherapy Side Effects in Cancer Patients: A Systematic Review and Meta-Analysis.Nutrients · 2023Pooled it
- Conditional eIF2A Deletion Suggests Extra-Adipose Mechanisms Underlying Metabolic Syndrome in Total-Body eIF2A Knockout Mice.FASEB bioAdvances · 2026Article
- Neuronal ketone body utilization couples exercise and time-restricted feeding to cognitive enhancement.Molecular metabolism · 2026Article
- Mitochondrial Dysfunction in Metabolic-Syndrome-Related MASLD/MASH: Metabolic Mechanisms and Therapeutic Perspectives.Metabolites · 2026Review
- IL-10 attenuates metabolic dysfunction-associated steatotic liver disease via modulation of hepatic responses to lipotoxicity.JCI insight · 2026Article
- Diet-Dependent Cognitive Benefits of Exogenous Ketone Body Precursor, (R,S)-1,3,-Butanediol, in a Mouse Model of Tauopathy.bioRxiv : the preprint server for biology · 2026Article
- Hepatic ketogenesis is not required for exercise training to mitigate diet-induced liver steatosis in male mice.Function (Oxford, England) · 2026Article
- Cognitive impairment caused by compromised hepatic ketogenesis is prevented by endurance exercise.The Journal of physiology · 2026Article
- Neuronal ketone body utilization couples exercise and time-restricted feeding to cognitive enhancement.bioRxiv : the preprint server for biology · 2026Article
- Hepatic ketogenesis supports liver lipid homeostasis during acute exercise but is not required for exercise training to mitigate liver steatosis in mice.bioRxiv : the preprint server for biology · 2026Article
- Hepatic HMGCS2-derived β-hydroxybutyrate attenuates hippocampal insulin resistance and neuroinflammation to promote MASLD-induced cognitive function.Communications biology · 2026Article
- Higher visceral fat area is inversely associated with ketosis in Chinese patients with type 2 diabetes mellitus: a cross-sectional study.Frontiers in endocrinology · 2026Article
- Neuroprotective and Cognitive Benefits of a Ketogenic Diet in a Type 2 Diabetes Rat Model.Molecular neurobiology · 2025Article
- Ketone metabolites in metabolic dysfunction-associated steatotic liver disease progression: optimizing keto-therapeutic strategies.American journal of physiology. Endocrinology and metabolism · 2025Review
- The neglected PCK1/glucagon (inter)action in nutrient homeostasis beyond gluconeogenesis: Disease pathogenesis and treatment.Molecular metabolism · 2025Review
- Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.Science advances · 2025Article
- Restoration of HMGCS2-mediated ketogenesis alleviates tacrolimus-induced hepatic lipid metabolism disorder.Acta pharmacologica Sinica · 2024Article
- Relationship between serum β-hydroxybutyrate and hepatic fatty acid oxidation in individuals with obesity and NAFLD.American journal of physiology. Endocrinology and metabolism · 2024Article
- Myosteatosis: Diagnosis, pathophysiology and consequences in metabolic dysfunction-associated steatotic liver disease.JHEP reports : innovation in hepatology · 2024Review
- Targeting ketone body metabolism to treat fatty liver disease.Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques · 2024Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
Abstract
While several molecular targets are under consideration, mechanistic underpinnings of the transition from uncomplicated nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) remain unresolved. Here we apply multiscale chemical profiling technologies to mouse models of deranged hepatic ketogenesis to uncover potential NAFLD driver signatures. Use of stable-isotope tracers, quantitatively tracked by nuclear magnetic resonance (NMR) spectroscopy, supported previous observations that livers of wild-type mice maintained long term on a high-fat diet (HFD) exhibit a marked increase in hepatic energy charge. Fed-state ketogenesis rates increased nearly 3-fold in livers of HFD-fed mice, a greater proportionate increase than that observed for tricarboxylic acid (TCA) cycle flux, but both of these contributors to overall hepatic energy homeostasis fueled markedly increased hepatic glucose production (HGP). Thus, to selectively determine the role of the ketogenic conduit on HGP and oxidative hepatic fluxes, we studied a ketogenesis-insufficient mouse model generated by knockdown of the mitochondrial isoform of 3-hydroxymethylglutaryl-CoA synthase (HMGCS2). In response to ketogenic insufficiency, TCA cycle flux in the fed state doubled and HGP increased more than 60%, sourced by a 3-fold increase in glycogenolysis. Finally, high-resolution untargeted metabolomics and shotgun lipidomics performed using ketogenesis-insufficient livers in the fed state revealed accumulation of bis(monoacylglycero)phosphates, which also accumulated in livers of other models commonly used to study NAFLD. In summary, natural and interventional variations in ketogenesis in the fed state strongly influence hepatic energy homeostasis, glucose metabolism, and the lipidome. Importantly, HGP remains tightly linked to overall hepatic energy charge, which includes both terminal fat oxidation through the TCA cycle and partial oxidation via ketogenesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.