Mitochondrial Homeostasis in Obesity-related Hypertriglyceridemia

Mela, Virginia; Ruiz-Limón, P.; Balongo, Manuel; Rad, Hanieh Motahari; Subiri, Alba; González-Jiménez, A.; Soler, Rocio; Ocaña, Luis Fernando Oñate; Azzouzi, Hamid el; Tinahones, Francisco J.; Valdivielso, Pedro; Murri, Mora

doi:10.1210/clinem/dgac332

Cited by 4 publications

(3 citation statements)

References 46 publications

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“…Previous studies showed that ketone bodies are potent inducers of mitochondrial biogenesis by upregulating the expression of the transcription factor, PGC1α 36 , 37 . Because mitochondrial homeostasis including biogenesis and function is key in regulating lipid metabolism 38 , we assessed whether impaired ketogenesis affected mitochondrial homeostasis in Hmgcs2 ΔLiv mice. We found no difference in the mRNA expression of Pgc1α, Nrf2, and various other mitochondria-associated genes such as Atp6, Cox1, and Nd4 in Hmgcs2 ΔLiv mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Hepatic ketogenesis regulates lipid homeostasis via ACSL1-mediated fatty acid partitioning

Ramakrishnan,

Mooli,

Han

et al. 2023

Preprint

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Liver-derived ketone bodies play a crucial role in fasting energy homeostasis by fueling the brain and peripheral tissues. Ketogenesis also acts as a conduit to remove excess acetyl-CoA generated from fatty acid oxidation and protects against diet-induced hepatic steatosis. Surprisingly, no study has examined the role of ketogenesis in fasting-associated hepatocellular lipid metabolism. Ketogenesis is driven by the rate-limiting mitochondrial enzyme 3-hydroxymethylglutaryl CoA synthase (HMGCS2) abundantly expressed in the liver. Here, we show that ketogenic insufficiency via disruption of hepatic HMGCS2 exacerbates liver steatosis in fasted chow and high-fat-fed mice. We found that the hepatic steatosis is driven by increased fatty acid partitioning to the endoplasmic reticulum (ER) for re-esterification via acyl-CoA synthetase long-chain family member 1 (ACSL1). Mechanistically, acetyl-CoA accumulation from impaired hepatic ketogenesis is responsible for the elevated translocation of ACSL1 to the ER. Moreover, we show increased ER-localized ACSL1 and re-esterification of lipids in human NASH displaying impaired hepatic ketogenesis. Finally, we show that L-carnitine, which buffers excess acetyl-CoA, decreases the ER-associated ACSL1 and alleviates hepatic steatosis. Thus, ketogenesis via controlling hepatocellular acetyl-CoA homeostasis regulates lipid partitioning and protects against hepatic steatosis.

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Section: Resultsmentioning

confidence: 99%

Hepatic ketogenesis regulates lipid homeostasis via ACSL1-mediated fatty acid partitioning

Ramakrishnan,

Mooli,

Han

et al. 2023

Preprint

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show abstract

“…114 As mitochondria play an essential role in human metabolism and energy homeostasis, mitochondrial dysfunction is associated with the pathophysiology of metabolic diseases. [115][116][117] It is noteworthy that exercise training is able to induce beneficial mitochondrial adaptations, including enhanced mitochondrial content, protein synthesis, oxidative capacity, or biogenesis, as well as the more efficient removal of dysfunctional/damaged mitochondria, with derived benefits in metabolic health. 118,119 Indeed, these adaptations appear to be exercise modality dependent 120 and may also be affected by other factors, such as training volume or intensity.…”

Section: Mitochondrial Fitnessmentioning

confidence: 99%

“…Furthermore, beyond their bioenergetic function, mitochondria are a hub for the generation of biosynthetic precursors, maintenance of redox balance, and management of metabolic waste 114 . As mitochondria play an essential role in human metabolism and energy homeostasis, mitochondrial dysfunction is associated with the pathophysiology of metabolic diseases 115–117 . It is noteworthy that exercise training is able to induce beneficial mitochondrial adaptations, including enhanced mitochondrial content, protein synthesis, oxidative capacity, or biogenesis, as well as the more efficient removal of dysfunctional/damaged mitochondria, with derived benefits in metabolic health 118,119 .…”

Section: Mechanisms Behind the Effects Of Time‐based Exercise On Meta...mentioning

confidence: 99%

Effects of exercise timing on metabolic health

et al. 2023

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SummaryThe increasing prevalence of metabolic syndrome is associated with major health and socioeconomic consequences. Currently, physical exercise, together with dietary interventions, is the mainstay of the treatment of obesity and related metabolic complications. Although exercise training includes different modalities, with variable intensity, duration, volume, or frequency, which may have a distinct impact on several characteristics related to metabolic syndrome, the potential effects of exercise timing on metabolic health are yet to be fully elucidated. Remarkably, promising results with regard to this topic have been reported in the last few years. Similar to other time‐based interventions, including nutritional therapy or drug administration, time‐of‐day‐based exercise may become a useful approach for the management of metabolic disorders. In this article, we review the role of exercise timing in metabolic health and discuss the potential mechanisms that could drive the metabolic‐related benefits of physical exercise performed in a time‐dependent manner.

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