Bilirubin: A Ligand of the PPARα Nuclear Receptor

Hong, Stephen; Gordon, Darren M.; Stec, David E.; HindsJr, Terry D.

doi:10.1007/978-3-030-78315-0_17

Cited by 5 publications

(10 citation statements)

References 143 publications

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“…Three essential enzymes, acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and stearoyl-CoA desaturase-1 (SCD1), regulate de novo lipogenesis in the liver ( Figure 3 ). ACC governs the conversion of acetyl-CoA to malonyl-CoA, which is converted to palmitate by FAS [ 64 ]. SCD1 catalyzes the formation of oleate and palmitoleate from stearoyl-CoA and palmitoyl-CoA [ 64 ].…”

Section: Molecular Mechanisms Of Lipid Accumulation In Mafldmentioning

confidence: 99%

“…ACC governs the conversion of acetyl-CoA to malonyl-CoA, which is converted to palmitate by FAS [ 64 ]. SCD1 catalyzes the formation of oleate and palmitoleate from stearoyl-CoA and palmitoyl-CoA [ 64 ]. These newly generated fatty acids can undergo a wide variety of biological modifications, including desaturation, elongation, and esterification, before either being stored as triglycerides or exported as VLDL particles [ 42 , 65 ].…”

Section: Molecular Mechanisms Of Lipid Accumulation In Mafldmentioning

confidence: 99%

“…These newly generated fatty acids can undergo a wide variety of biological modifications, including desaturation, elongation, and esterification, before either being stored as triglycerides or exported as VLDL particles [ 42 , 65 ]. The levels of these two proteins can increase hepatic steatosis and hypertriglyceridemia [ 64 ]. Moreover, increased production of palmitate may lead to steatohepatitis through increases in inflammation and apoptosis [ 66 ].…”

Section: Molecular Mechanisms Of Lipid Accumulation In Mafldmentioning

confidence: 99%

“…Enhanced de novo lipogenesis is responsible for a portion of the lipid accumulation in MAFLD and the buildup of toxic lipid species such as ceramides that may promote the transition to NASH. However, care must be taken when proposing blocking specific enzymes in the de novo lipogenesis pathway, as this could promote the accumulation of more toxic lipids [ 64 ]. Further studies are needed before this pathway should be considered as a potential therapeutic target for the treatment of MAFLD as there may be major side effects from blockade of normal lipid processing.…”

Section: Molecular Mechanisms Of Lipid Accumulation In Mafldmentioning

confidence: 99%

“…Oxidation of fatty acids primarily occurs in the mitochondria; however, oxidation of very long-chain fatty acids commences in the peroxisomes and then is finally processed in the mitochondria ( Figure 3 ) [ 64 ]. In cases of lipid overload, as seen in obesity, ω-oxidation by cytochrome P450 enzymes also contributes to fatty acid oxidation.…”

Section: Molecular Mechanisms Of Lipid Accumulation In Mafldmentioning

confidence: 99%

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Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways

et al. 2022

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The metabolic-associated fatty liver disease (MAFLD) is a condition of fat accumulation in the liver in combination with metabolic dysfunction in the form of overweight or obesity and insulin resistance. It is also associated with an increased cardiovascular disease risk, including hypertension and atherosclerosis. Hepatic lipid metabolism is regulated by a combination of the uptake and export of fatty acids, de novo lipogenesis, and fat utilization by β-oxidation. When the balance between these pathways is altered, hepatic lipid accumulation commences, and long-term activation of inflammatory and fibrotic pathways can progress to worsen the liver disease. This review discusses the details of the molecular mechanisms regulating hepatic lipids and the emerging therapies targeting these pathways as potential future treatments for MAFLD.

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Section: Molecular Mechanisms Of Lipid Accumulation In Mafldmentioning

confidence: 99%

Section: Molecular Mechanisms Of Lipid Accumulation In Mafldmentioning

confidence: 99%

Section: Molecular Mechanisms Of Lipid Accumulation In Mafldmentioning

confidence: 99%

Section: Molecular Mechanisms Of Lipid Accumulation In Mafldmentioning

confidence: 99%

Section: Molecular Mechanisms Of Lipid Accumulation In Mafldmentioning

confidence: 99%

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Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways

et al. 2022

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Glucocorticoids, their uses, sexual dimorphisms, and diseases: new concepts, mechanisms, and discoveries

Martinez,

Appleton,

Kipp

et al. 2024

Physiological Reviews

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The normal stress response in humans is governed by the hypothalamic-pituitary-adrenal (HPA) axis through heightened mechanisms during stress, raising blood levels of the glucocorticoid hormone cortisol. Glucocorticoids are quintessential compounds that balance the proper functioning of numerous systems in the mammalian body. They are also generated synthetically and are the preeminent therapy for inflammatory diseases. They act by binding to the nuclear receptor transcription factor, the glucocorticoid receptor (GR), which has two main isoforms (GRα and GRβ). Our classical understanding of glucocorticoid signaling is from the GRα isoform, which binds the hormone, whereas GRβ has no known ligands. With glucocorticoids being involved in many physiological and cellular processes, even small disruptions in their release via the HPA axis, or changes in GR isoform expression, can have dire ramifications on health. Long-term chronic glucocorticoid therapy can lead to a glucocorticoid-resistant state, and we deliberate how this impacts disease treatment. Chronic glucocorticoid treatment can lead to noticeable side effects such as weight gain, adiposity, diabetes, and others that we discuss in detail. There are sexually dimorphic responses to glucocorticoids, and women tend to have a more hyperresponsive HPA axis than men. This review summarizes our understanding of glucocorticoids, critically analyzes the GR isoforms and their beneficial and deleterious mechanisms, and the sexual differences that cause a dichotomy in responses. We also discuss the future of glucocorticoid therapy and propose a new concept of dual GR isoform agonist and postulate why activating both isoforms may prevent glucocorticoid resistance.

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Metabolic-Dysfunction Associated Steatotic Liver Disease -Its Pathophysiology, Association with Atherosclerosis and Cardiovascular Disease, and Ideal Treatments

Yanai,

Adachi,

Hakoshima

et al. 2023

Preprint

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Metabolic-dysfunction associated steatotic liver disease (MASLD) is a chronic liver disease that affects more than a quarter of the global population, and is increasing worldwide, due to the pandemic of obesity. Insulin resistance is closely associated with the development and progression of MASLD. Hepatic entry of increased fatty acids (FA) released from adipose tissue, increase in FA synthesis and reduced FA oxidation in the liver, and hepatic overproduction of triglyceride (TG)-rich lipoproteins may induce the development of MASLD. Since insulin resistance also induces atherosclerosis, the leading cause for death in MASLD patients is cardiovascular disease (CVD). Considering that the development of CVD determines the prognosis of MASLD patients, the ideal therapeutic interventions for MASLD should reduce body weight, improve coronary risk factors, in addition to an improvement in liver functiom. Lifestyle modification such as diet and exercise and surgical interventions such as bariatric surgery and intragastric balloons have shown to improve MASLD by reducing body weight. Sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to improve coronary risk factors and to suppress the occurrence of CVD. Both SGLT2i and GLP-1 have been reported to improve liver enzymes, hepatic steatosis and fibrosis. We recently reported that the selective peroxisome proliferator-activated receptor-alpha (PPARα) modulator, pemafibrate, improved liver function. PPARα agonists have multiple anti-atherogenic properties. Here, we consider the pathophysiology of MASLD and the mechanisms of action of such drugs, and consider whether such drugs and the combination therapy of such drugs could be the ideal treatments for MASLD.

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Bilirubin: A Ligand of the PPARα Nuclear Receptor

Cited by 5 publications

References 143 publications

Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways

Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways

Glucocorticoids, their uses, sexual dimorphisms, and diseases: new concepts, mechanisms, and discoveries

Metabolic-Dysfunction Associated Steatotic Liver Disease -Its Pathophysiology, Association with Atherosclerosis and Cardiovascular Disease, and Ideal Treatments

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