Ketone body production is differentially altered in steatosis and non‐alcoholic steatohepatitis in obese humans

Männistö, Ville; Simonen, Marko; Hyysalo, Jenni; Soininen, Pasi; Kangas, Antti J.; Kaminska, Dorota; Matte, Ananda K.; Venesmaa, Sari; Käkelä, Pirjo; Kärjä, Vesa; Arola, Johanna; Gylling, Helena; Cederberg, Henna; Kuusisto, Johanna; Laakso, Markku; Yki‐Järvinen, Hannele; Ala‐Korpela, Mika

doi:10.1111/liv.12769

Cited by 64 publications

(57 citation statements)

References 45 publications

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“…In particular, CREB3L3 plays a role in exogenous (dietary) fatty acid homeostasis, while PPARα plays dual roles in exogenous and endogenous (released from lipolysis in adipose tissues) fatty acid homeostasis. Individuals with NASH have been shown to have lower levels of ketone bodies than individuals with simple steatosis38, and studies on humans have revealed that the levels of plasma ketone bodies is negatively correlated with the pathology of NASH, suggesting a reduction in ketone body metabolism in individuals with NASH38. Thus, as ketogenesis prevents diet-induced fatty liver injury and hyperglycaemia37, CREB3L3 may represent a new therapeutic target for NAFLD.…”

Section: Discussionmentioning

confidence: 99%

CREB3L3 controls fatty acid oxidation and ketogenesis in synergy with PPARα

Nakagawa

Satoh

Tezuka

et al. 2016

Sci Rep

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CREB3L3 is involved in fatty acid oxidation and ketogenesis in a mutual manner with PPARα. To evaluate relative contribution, a combination of knockout and transgenic mice was investigated. On a ketogenic-diet (KD) that highlights capability of hepatic ketogenesis, Creb3l3−/− mice exhibited reduction of expression of genes for fatty oxidation and ketogenesis comparable to Ppara−/− mice. Most of the genes were further suppressed in double knockout mice indicating independent contribution of hepatic CREB3L3. During fasting, dependency of ketogenesis on CREB3L3 is lesser extents than Ppara−/− mice suggesting importance of adipose PPARα for supply of FFA and hyperlipidemia in Creb3l3−/− mice. In conclusion CREB3L3 plays a crucial role in hepatic adaptation to energy starvation via two pathways: direct related gene regulation and an auto-loop activation of PPARα. Furthermore, as KD-fed Creb3l3−/− mice exhibited severe fatty liver, activating inflammation, CREB3L3 could be a therapeutic target for NAFLD.

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Section: Discussionmentioning

confidence: 99%

CREB3L3 controls fatty acid oxidation and ketogenesis in synergy with PPARα

Nakagawa

Satoh

Tezuka

et al. 2016

Sci Rep

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“…Through incompletely defined mechanisms, hyperinsulinemia suppresses ketogenesis, possibly contributing to hypoketonemia compared to lean controls (Bergman et al, 2007; Bickerton et al, 2008; Satapati et al, 2012; Soeters et al, 2009; Sunny et al, 2011; Vice et al, 2005). Nonetheless, the ability of circulating ketone body concentrations to predict NAFLD is controversial (Männistö et al, 2015; Sanyal et al, 2001). Robust quantitative magnetic resonance spectroscopic methods in animal models revealed increased ketone turnover rate with moderate insulin resistance, but decreased rates were evident with more severe insulin resistance (Satapati et al, 2012; Sunny et al, 2010).…”

Section: Non-alcoholic Fatty Liver Disease (Nafld) and Ketone Body Mementioning

confidence: 99%

“…Taken together, future experiments are required to address mechanisms through which relative ketogenic insufficiency may become maladaptive, contribute to hyperglycemia, provoke steatohepatitis, and whether these mechanisms are operant in human NAFLD/NASH. As epidemiological evidence suggests impaired ketogenesis during the progression of steatohepatitis (Embade et al, 2016; Marinou et al, 2011; Männistö et al, 2015; Pramfalk et al, 2015; Safaei et al, 2016) therapies that increase hepatic ketogenesis could prove salutary (Degirolamo et al, 2016; Honda et al, 2016). …”

Section: Non-alcoholic Fatty Liver Disease (Nafld) and Ketone Body Mementioning

confidence: 99%

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

2017

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Ketone body metabolism is a central node in physiological homeostasis. In this review, we discuss how ketones serve discrete fine-tuning metabolic roles that optimize organ and organism performance in varying nutrient states, and protect from inflammation and injury in multiple organ systems. Traditionally viewed as metabolic substrates enlisted only in carbohydrate restriction, recent observations underscore the importance of ketone bodies as vital metabolic and signaling mediators when carbohydrates are abundant. Complementing a repertoire of known therapeutic options for diseases of the nervous system, prospective roles for ketone bodies in cancer have arisen, as have intriguing protective roles in heart and liver, opening therapeutic options in obesity-related and cardiovascular disease. Controversies in ketone metabolism and signaling are discussed to reconcile classical dogma with contemporary observations.

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“…In fatty liver disease, hepatic beta-oxidation and ketogenesis are upregulated (Sunny et al 2010, Mannisto et al 2015. Hepatic beta-oxidation in response to lipid accumulation prevents lipotoxicity and supports gluconeogenesis and ketogenesis.…”

Section: Beta-oxidation and Ketogenesismentioning

confidence: 99%

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Geisler

Renquist

2017

Journal of Endocrinology

146

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Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.

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Ketone body production is differentially altered in steatosis and non‐alcoholic steatohepatitis in obese humans

Abstract: Lower levels of ketone bodies in individuals with NASH compared to individuals with simple steatosis suggest a decrease in ketone body metabolism in NASH.

Cited by 64 publications

References 45 publications

CREB3L3 controls fatty acid oxidation and ketogenesis in synergy with PPARα

CREB3L3 controls fatty acid oxidation and ketogenesis in synergy with PPARα

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

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