Lipogenesis inhibitors: therapeutic opportunities and challenges

Nature Reviews Drug Discovery, Год журнала: 2022, Номер 21(4), С. 283 - 305

Опубликована: Янв. 14, 2022

Fatty acids are essential for survival, acting as bioenergetic substrates, structural components and signalling molecules. Given their vital role, cells have evolved mechanisms to generate fatty from alternative carbon sources, through a process known de novo lipogenesis (DNL). Despite the importance of DNL, aberrant upregulation is associated with wide variety pathologies. Inhibiting core enzymes including citrate/isocitrate carrier (CIC), ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC) acid synthase (FAS), represents an attractive therapeutic strategy. challenges related efficacy, selectivity safety, several new classes synthetic DNL inhibitors entered clinical-stage development may become foundation class therapeutics. De (DNL) maintenance whole-body cellular homeostasis, but pathway broad range conditions, cardiovascular disease, metabolic disorders cancers. Here, Steinberg colleagues provide overview physiological pathological roles assess strategies agents currently in therapeutically target them.

Язык: Английский

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Current status and future trends of the global burden of MASLD

Trends in Endocrinology and Metabolism, Год журнала: 2024, Номер 35(8), С. 697 - 707

Опубликована: Фев. 29, 2024

Язык: Английский

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Hepatic cholesterol transport and its role in non-alcoholic fatty liver disease and atherosclerosis

Progress in Lipid Research, Год журнала: 2021, Номер 83, С. 101109 - 101109

Опубликована: Июнь 11, 2021

Язык: Английский

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Pathophysiological Molecular Mechanisms of Obesity: A Link between MAFLD and NASH with Cardiovascular Diseases

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(21), С. 11629 - 11629

Опубликована: Окт. 27, 2021

Obesity is now a worldwide epidemic ensuing an increase in comorbidities' prevalence, such as insulin resistance, type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular (CVD), autoimmune diseases, and some cancers, CVD being one of the main causes death world. Several studies provide evidence for association between MAFLD atherosclerosis cardio-metabolic disorders, including CVDs coronary heart stroke. Therefore, combination MAFLD/NASH associated with vascular risk progression, but underlying mechanisms linking are still under investigation. may probably be involved, hepatic/systemic atherogenic dyslipidemia, well pro-atherogenic, pro-coagulant, pro-inflammatory mediators released from steatotic/inflamed liver. strongly which involved its pathogenesis progression to NASH. Insulin resistance major factor subjects without diabetes. However, T2D has been considered most common link CVD. This review summarizes obesity MAFLD, NASH, CVD, considering pathophysiological molecular these diseases. We also discuss NASH development structural functional cardiac alterations, pharmacological strategies treat prevention.

Язык: Английский

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Metabolic-associated Fatty Liver Disease (MAFLD): A Multi-systemic Disease Beyond the Liver

Journal of Clinical and Translational Hepatology, Год журнала: 2021, Номер 10(2), С. 329 - 338

Опубликована: Окт. 19, 2021

Nonalcoholic fatty liver disease (NAFLD) is a multisystemic clinical condition that presents with wide spectrum of extrahepatic manifestations, such as obesity, type 2 diabetes mellitus, metabolic syndrome, cardiovascular diseases, chronic kidney disease, malignancies, cognitive disorders, and polycystic ovarian syndrome. Among NAFLD patients, the most common mortality etiology followed by liver-related complications. Furthermore, severity diseases parallel to NAFLD. In practice, awareness associations concomitant major importance for initiating prompt timely screening multidisciplinary management spectrum. 2020, consensus from 22 countries redefined (dysfunction)-associated (MAFLD), which resulted in redefinition corresponding population. Although patients diagnosed MAFLD mostly overlap, populations are not identical. this review, we compared key between MAFLD.

Язык: Английский

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An international Delphi consensus statement on metabolic dysfunction-associated fatty liver disease and risk of chronic kidney disease

HepatoBiliary Surgery and Nutrition, Год журнала: 2023, Номер 12(3), С. 386 - 403

Опубликована: Фев. 24, 2023

With the rising global prevalence of fatty liver disease related to metabolic dysfunction, association this common condition with chronic kidney (CKD) has become increasingly evident. In 2020, more inclusive term dysfunction-associated (MAFLD) was proposed replace non-alcoholic (NAFLD). The observed between MAFLD and CKD our understanding that can be a consequence underlying dysfunction support notion individuals are at higher risk having developing compared those without MAFLD. However, date, there is no appropriate guidance on in Furthermore, been little attention paid link Nephrology community.Using Delphi-based approach, multidisciplinary panel 50 international experts from 26 countries reached consensus some open research questions regarding CKD.This statement provided epidemiology, mechanisms, management treatment CKD, as well relationship severity which establish framework for early prevention these two interconnected diseases.

Язык: Английский

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Non-alcoholic Fatty Liver Disease (NAFLD), Type 2 Diabetes, and Non-viral Hepatocarcinoma: Pathophysiological Mechanisms and New Therapeutic Strategies

Biomedicines, Год журнала: 2023, Номер 11(2), С. 468 - 468

Опубликована: Фев. 6, 2023

In recent years, the incidence of non-viral hepatocellular carcinoma (HCC) has increased dramatically, which is probably related to prevalence metabolic syndrome, together with obesity and type 2 diabetes mellitus (T2DM). Several epidemiological studies have established association between T2DM HCC demonstrated role as an independent risk factor for development HCC. The pathophysiological mechanisms underlying Non-alcoholic fatty liver disease (NAFLD) its progression steatohepatitis (NASH) cirrhosis are various involve pro-inflammatory agents, oxidative stress, apoptosis, adipokines, JNK-1 activation, IGF-1 activity, immunomodulation, alteration gut microbiota. Moreover, these thought play a significant in NAFLD-related carcinoma. Early diagnosis timely correction factors essential prevent onset fibrosis purpose this review summarize current evidence on among obesity, NASH/NAFLD, T2DM, HCC, emphasis clinical impact. addition, we will examine main complex relationship, promising strategies that recently emerged diseases’ treatments.

Язык: Английский

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The Multifaceted Roles of Macrophages in NAFLD Pathogenesis

Cellular and Molecular Gastroenterology and Hepatology, Год журнала: 2023, Номер 15(6), С. 1311 - 1324

Опубликована: Янв. 1, 2023

Nonalcoholic fatty liver disease (NAFLD) is the manifestation of metabolic syndrome. NAFLD constitutes a spectrum pathologies ranging from simple hepatic steatosis (nonalcoholic liver) to more progressive form steatohepatitis and fibrosis, which can culminate in cirrhosis hepatocellular carcinoma. Macrophages play multiple roles context pathogenesis by regulating inflammatory responses homeostasis thereby may represent an attractive therapeutic target. Advances high-resolution methods have highlighted extraordinary heterogeneity plasticity macrophage populations activation states thereof. Harmful/disease-promoting as well beneficial/restorative phenotypes co-exist are dynamically regulated, thus this complexity must be taken into consideration strategies concerning targeting. Macrophage includes their distinct ontogeny (embryonic Kupffer cells vs bone marrow-/monocyte-derived macrophages) functional phenotype, for example, phagocytes, lipid- scar-associated macrophages, or restorative macrophages. Here, we discuss multifaceted role macrophages steatosis, steatohepatitis, transition fibrosis carcinoma, focusing on both beneficial maladaptive functions at different stages. We also highlight systemic aspect dysregulation illustrate contribution reciprocal crosstalk between organs compartments (eg, gut-liver axis, adipose tissue, cardiohepatic interactions). Furthermore, current state development pharmacologic treatment options targeting biology.

Язык: Английский

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Systemic impacts of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) on heart, muscle, and kidney related diseases

Frontiers in Cell and Developmental Biology, Год журнала: 2024, Номер 12

Опубликована: Июль 16, 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty (NAFLD), is the most common disorder worldwide, with an estimated global prevalence of more than 31%. steatohepatitis (MASH), formerly (NASH), a progressive form MASLD characterized by hepatic steatosis, inflammation, and fibrosis. This review aims to provide comprehensive analysis extrahepatic manifestations MASH, focusing on chronic diseases related cardiovascular, muscular, renal systems. A systematic published studies literature was conducted summarize findings systemic impacts MASH. The focused association MASH metabolic comorbidities, cardiovascular mortality, sarcopenia, kidney disease. Mechanistic insights into concept lipotoxic inflammatory "spill over" from MASH-affected were also explored. are highly associated (50%-80%) other comorbidities such impaired insulin response, type 2 diabetes, dyslipidemia, hypertriglyceridemia, hypertension. Furthermore, 90% obese patients diabetes have Data suggest that in middle-aged individuals (especially those aged 45-54), independent risk factor for plays crucial role mediating pathological effects observed. Understanding multifaceted impact heart, muscle, early detection stratification. knowledge timely implementing management strategies addressing multi-organ involvement pathogenesis.

Язык: Английский

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The pan-PPAR agonist lanifibranor improves cardiometabolic health in patients with metabolic dysfunction-associated steatohepatitis

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Май 10, 2024

Abstract Lanifibranor, a pan-PPAR agonist, improves liver histology in patients with metabolic dysfunction-associated steatohepatitis (MASH), who have poor cardiometabolic health (CMH) and cardiovascular events as major mortality cause. NATIVE trial secondary exploratory outcomes (ClinicalTrials.gov NCT03008070) were analyzed for the effect of lanifibranor on IR, lipid glucose metabolism, systemic inflammation, blood pressure (BP), hepatic steatosis (imaging histological grading) all original analysis. With lanifibranor, triglycerides, HDL-C, apolipoproteins, insulin, HOMA-IR, HbA1c, fasting (FG), hs-CRP, ferritin, diastolic BP improved significantly, independent diabetes status: most prediabetes returned to normal FG levels. Significant adiponectin increases correlated CMH marker improvement; had an average weight gain 2.5 kg, 49% gaining ≥2.5% weight. Therapeutic benefits similar regardless change. Here, we show that effects MASH are accompanied improvement, indicative potential clinical benefits.

Язык: Английский

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