A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis

Loft, Anne; Schmidt, Søren Fisker; Caratti, Giorgio; Stifel, Ulrich; Havelund, Jesper Foged; Sekar, Revathi; Kwon, Yongseok; Sulaj, Alba; Chow, Kan Kau; Alfaro, Ana Jimena; Schwarzmayr, Thomas; Rittig, Nikolaj; Svart, Mads; Tsokanos, Foivos-Filippos; Maida, Adriano; Blutke, Andreas; Feuchtinger, Annette; Møller, Niels; Blüher, Matthias; Nawroth, Peter P.; Szendrödi, Julia; Færgeman, Nils J.; Zeigerer, Anja; Tuckermann, Jan; Herzig, Stephan

doi:10.1016/j.cmet.2022.01.004

Cited by 39 publications

(31 citation statements)

References 61 publications

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“…For the DIO model, eight-week-old male C57BL/6J mice were fed with a 60 kcal% high-fat diet (HFD, D12492; Research Diets) for 16 weeks ( 18 , 19 ). For the fasting model, food was removed before lights off for 24h ( 20 , 21 ). For PTH treatment, mice were subcutaneously injected with PTH peptide (synthesized by KE Biochem Co. Ltd) at the dose of 40 μg/kg/day during the experiment ( 22 – 26 ), and the control group was injected with an equal volume of PBS.…”

Section: Methodsmentioning

confidence: 99%

Parathyroid hormone alleviates non-alcoholic liver steatosis via activating the hepatic cAMP/PKA/CREB pathway

Xiao

Guo

et al. 2022

Front. Endocrinol.

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Non-alcoholic fatty liver disease (NAFLD), hallmarked by liver steatosis, is becoming a global concern, but effective and safe drugs for NAFLD are still lacking at present. Parathyroid hormone (PTH), the only FDA-approved anabolic treatment for osteoporosis, is important in calcium-phosphate homeostasis. However, little is known about its potential therapeutic effects on other diseases. Here, we report that intermittent administration of PTH ameliorated non-alcoholic liver steatosis in diet-induced obese (DIO) mice and db/db mice, as well as fasting-induced hepatic steatosis. In vitro, PTH inhibits palmitic acid-induced intracellular lipid accumulation in a parathyroid hormone 1 receptor (PTH1R)-dependent manner. Mechanistically, PTH upregulates the expression of genes involved in lipid β-oxidation and suppresses the expression of genes related to lipid uptake and de novo lipogenesis by activating the cAMP/PKA/CREB pathway. Taken together, our current finding proposes a new therapeutic role of PTH on NAFLD.

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Section: Methodsmentioning

confidence: 99%

Parathyroid hormone alleviates non-alcoholic liver steatosis via activating the hepatic cAMP/PKA/CREB pathway

Xiao

Guo

et al. 2022

Front. Endocrinol.

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“…Another small study of 11 overweight adults participating in a 4-day randomized crossover study of TRF in which food was consumed either between 8 a.m. and 2 p.m. (early fasting) or 8 a.m. and 8 p.m. (control) demonstrated improved mean 24-h glucose levels and induced broad changes in circadian clock gene expression, as well as expression of hormones and genes related to longevity and autophagy in the early fasting group as compared to the control, implying anti-aging effects [ 34 ]. In a further delve into molecular mechanisms of IF, the hepatic macrophage glucocorticoid receptor was recently identified as an important component of fasting-induced macrophage secretion of inflammatory cytokines, and its relationship to influence of ketogenesis in hepatocytes was demonstrated [ 45 ].…”

Section: Potential Mechanisms Of Action For Intermittent Fasting Effectsmentioning

confidence: 99%

The Role of Intermittent Fasting in the Management of Nonalcoholic Fatty Liver Disease: A Narrative Review

Lavallee

Bruno

et al. 2022

Nutrients

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Intermittent fasting is a non-pharmacological dietary approach to management of obesity and metabolic syndrome, involving periodic intervals of complete or near-complete abstinence from food and energy-containing fluids. This dietary strategy has recently gained significant popularity in mainstream culture and has been shown to induce weight loss in humans, reduce gut and systemic inflammation, and improve gut microbial diversity and dysbiosis (largely in animal models). It has been hypothesized that intermittent fasting could be beneficial in the management of nonalcoholic fatty liver disease, given the condition’s association with obesity. This review summarizes protocols, potential mechanisms of action, and evidence for intermittent fasting in nonalcoholic fatty liver disease. It also highlights practical considerations for implementing intermittent fasting in clinical practice. A search of the literature for English-language articles related to intermittent fasting or time-restricted feeding and liver disease was completed in PubMed and Google Scholar. Potential mechanisms of action for effects of intermittent fasting included modulation of circadian rhythm, adipose tissue and adipokines, gut microbiome, and autophagy. Preclinical, epidemiological, and clinical trial data suggested clinical benefits of intermittent fasting on metabolic and inflammatory markers in humans. However, there was a paucity of evidence of its effects in patients with nonalcoholic fatty liver disease. More clinical studies are needed to determine mechanisms of action and to evaluate safety and efficacy of intermittent fasting in this population.

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“…The crosstalk of macrophage with hepatocytes is crucial for sustaining inflammatory signals during liver injury. In normal livers, macrophages contribute to normal hepatocytes function by regulating glucocorticoid signals ( 152 ). During liver inflammation, Kupffer cells and infiltrating macrophages express scavenger (SR) and pattern recognition receptors (PRR) to readily respond to pathogens and liver damage ( 153 ).…”

Section: Macrophage Reprogramming In Steatosis Driven Hccmentioning

confidence: 99%

Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis

Alba

Datta

et al. 2022

Front. Oncol.

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Obesity confers an independent risk for carcinogenesis. Classically viewed as a genetic disease, owing to the discovery of tumor suppressors and oncogenes, genetic events alone are not sufficient to explain the progression and development of cancers. Tumor development is often associated with metabolic and immunological changes. In particular, obesity is found to significantly increase the mortality rate of liver cancer. As its role is not defined, a fundamental question is whether and how metabolic changes drive the development of cancer. In this review, we will dissect the current literature demonstrating that liver lipid dysfunction is a critical component driving the progression of cancer. We will discuss the involvement of inflammation in lipid dysfunction driven liver cancer development with a focus on the involvement of liver macrophages. We will first discuss the association of steatosis with liver cancer. This will be followed with a literature summary demonstrating the importance of inflammation and particularly macrophages in the progression of liver steatosis and highlighting the evidence that macrophages and macrophage produced inflammatory mediators are critical for liver cancer development. We will then discuss the specific inflammatory mediators and their roles in steatosis driven liver cancer development. Finally, we will summarize the molecular pattern (PAMP and DAMP) as well as lipid particle signals that are involved in the activation, infiltration and reprogramming of liver macrophages. We will also discuss some of the therapies that may interfere with lipid metabolism and also affect liver cancer development.

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A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis

Cited by 39 publications

References 61 publications

Parathyroid hormone alleviates non-alcoholic liver steatosis via activating the hepatic cAMP/PKA/CREB pathway

Parathyroid hormone alleviates non-alcoholic liver steatosis via activating the hepatic cAMP/PKA/CREB pathway

The Role of Intermittent Fasting in the Management of Nonalcoholic Fatty Liver Disease: A Narrative Review

Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis

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