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Nature Reviews. Endocrinology Aug 2023Ubiquitous yet unique, lipid droplets are intracellular organelles that are increasingly being recognized for their versatility beyond energy storage. Advances... (Review)
Review
Ubiquitous yet unique, lipid droplets are intracellular organelles that are increasingly being recognized for their versatility beyond energy storage. Advances uncovering the intricacies of their biogenesis and the diversity of their physiological and pathological roles have yielded new insights into lipid droplet biology. Despite these insights, the mechanisms governing the biogenesis and functions of lipid droplets remain incompletely understood. Moreover, the causal relationship between the biogenesis and function of lipid droplets and human diseases is poorly resolved. Here, we provide an update on the current understanding of the biogenesis and functions of lipid droplets in health and disease, highlighting a key role for lipid droplet biogenesis in alleviating cellular stresses. We also discuss therapeutic strategies of targeting lipid droplet biogenesis, growth or degradation that could be applied in the future to common diseases, such as cancer, hepatic steatosis and viral infection.
Topics: Humans; Lipid Droplets; Lipid Metabolism; Lipogenesis
PubMed: 37221402
DOI: 10.1038/s41574-023-00845-0 -
Journal of Hepatology Nov 2023The farnesoid X receptor (FXR), a bile acid (BA)-activated nuclear receptor highly expressed in the liver and intestine, regulates the expression of genes involved in... (Review)
Review
The farnesoid X receptor (FXR), a bile acid (BA)-activated nuclear receptor highly expressed in the liver and intestine, regulates the expression of genes involved in cholesterol and bile acid homeostasis, hepatic gluconeogenesis, lipogenesis, inflammation and fibrosis, in addition to controlling intestinal barrier integrity, preventing bacterial translocation and maintaining gut microbiota eubiosis. Non-alcoholic steatohepatitis (NASH), an advanced stage of non-alcoholic fatty liver disease, is characterized by hepatic steatosis, hepatocyte damage (ballooning) and inflammation, leading to fibrosis, cirrhosis and hepatocellular carcinoma. NASH represents a major unmet medical need, but no pharmacological treatments have yet been approved. The pleiotropic mechanisms involved in NASH development offer a range of therapeutic opportunities and among them FXR activation has emerged as an established pharmacological target. Various FXR agonists with different physicochemical properties, which can be broadly classified as BA derivatives, non-BA-derived steroidal FXR agonists, non-steroidal FXR agonists, and partial FXR agonists, are in advanced clinical development. In this review we will summarize key preclinical and clinical features of the most advanced FXR agonists and critically evaluate their potential in NASH treatment.
PubMed: 37562746
DOI: 10.1016/j.jhep.2023.07.034 -
Nature Biotechnology Nov 2023The lack of registered drugs for nonalcoholic fatty liver disease (NAFLD) is partly due to the paucity of human-relevant models for target discovery and compound...
The lack of registered drugs for nonalcoholic fatty liver disease (NAFLD) is partly due to the paucity of human-relevant models for target discovery and compound screening. Here we use human fetal hepatocyte organoids to model the first stage of NAFLD, steatosis, representing three different triggers: free fatty acid loading, interindividual genetic variability (PNPLA3 I148M) and monogenic lipid disorders (APOB and MTTP mutations). Screening of drug candidates revealed compounds effective at resolving steatosis. Mechanistic evaluation of effective drugs uncovered repression of de novo lipogenesis as the convergent molecular pathway. We present FatTracer, a CRISPR screening platform to identify steatosis modulators and putative targets using APOB and MTTP organoids. From a screen targeting 35 genes implicated in lipid metabolism and/or NAFLD risk, FADS2 (fatty acid desaturase 2) emerged as an important determinant of hepatic steatosis. Enhancement of FADS2 expression increases polyunsaturated fatty acid abundancy which, in turn, reduces de novo lipogenesis. These organoid models facilitate study of steatosis etiology and drug targets.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Drug Evaluation, Preclinical; Hepatocytes; Lipid Metabolism; Apolipoproteins B; Liver
PubMed: 36823355
DOI: 10.1038/s41587-023-01680-4 -
International Journal of Molecular... Jul 2023Macrophage polarization is influenced by lipids, which also exert significant control over macrophage functions. Lipids and their metabolites are players in intricate... (Review)
Review
Macrophage polarization is influenced by lipids, which also exert significant control over macrophage functions. Lipids and their metabolites are players in intricate signaling pathways that modulate macrophages' responses to pathogens, phagocytosis, ferroptosis, and inflammation. This review focuses on lipid metabolism and macrophage functions and addresses potential molecular targets for the treatment of macrophage-related diseases. While lipogenesis is crucial for lipid accumulation and phagocytosis in M1 macrophages, M2 macrophages likely rely on fatty acid β-oxidation to utilize fatty acids as their primary energy source. Cholesterol metabolism, regulated by factors such as SREBPs, PPARs, and LXRs, is associated with the cholesterol efflux capacity and the formation of foam cells (M2-like macrophages). Foam cells, which are targets for atherosclerosis, are associated with an increase in inflammatory cytokines. Lipolysis and fatty acid uptake markers, such as CD36, also contribute to the production of cytokines. Enhancing the immune system through the inhibition of lipid-metabolism-related factors can potentially serve as a targeted approach against tumor cells. Cyclooxygenase inhibitors, which block the conversion of arachidonic acid into various inflammatory mediators, influence macrophage polarization and have generated attention in cancer research.
Topics: Lipid Metabolism; Cell Polarity; Inflammation; Neoplasms; Macrophages; Cholesterol; Fatty Acids; Ferroptosis; Humans
PubMed: 37569407
DOI: 10.3390/ijms241512032 -
The Journal of Clinical Investigation Jan 2024Nonalcoholic fatty liver disease (NAFLD) encompasses a disease continuum from simple steatosis to nonalcoholic steatohepatitis (NASH). However, there are currently no...
Nonalcoholic fatty liver disease (NAFLD) encompasses a disease continuum from simple steatosis to nonalcoholic steatohepatitis (NASH). However, there are currently no approved pharmacotherapies for NAFLD, although several drugs are in advanced stages of clinical development. Because of the complex pathophysiology and heterogeneity of NAFLD, the identification of potential therapeutic targets is clinically important. Here, we demonstrated that tripartite motif 56 (TRIM56) protein abundance was markedly downregulated in the livers of individuals with NAFLD and of mice fed a high-fat diet. Hepatocyte-specific ablation of TRIM56 exacerbated the progression of NAFLD, while hepatic TRIM56 overexpression suppressed it. Integrative analyses of interactome and transcriptome profiling revealed a pivotal role of TRIM56 in lipid metabolism and identified the lipogenesis factor fatty acid synthase (FASN) as a direct binding partner of TRIM56. TRIM56 directly interacted with FASN and triggered its K48-linked ubiquitination-dependent degradation. Finally, using artificial intelligence-based virtual screening, we discovered an orally bioavailable small-molecule inhibitor of FASN (named FASstatin) that potentiates TRIM56-mediated FASN ubiquitination. Therapeutic administration of FASstatin improved NAFLD and NASH pathologies in mice with an optimal safety, tolerability, and pharmacokinetics profile. Our findings provide proof of concept that targeting the TRIM56/FASN axis in hepatocytes may offer potential therapeutic avenues to treat NAFLD.
Topics: Animals; Mice; Artificial Intelligence; Diet, High-Fat; Fatty Acid Synthases; Non-alcoholic Fatty Liver Disease
PubMed: 38206764
DOI: 10.1172/JCI166149 -
Nature Metabolism Oct 2023Under normal conditions, insulin promotes hepatic de novo lipogenesis (DNL). However, during insulin resistance (IR), when insulin signalling is blunted and accompanied...
Under normal conditions, insulin promotes hepatic de novo lipogenesis (DNL). However, during insulin resistance (IR), when insulin signalling is blunted and accompanied by hyperinsulinaemia, the promotion of hepatic DNL continues unabated and hepatic steatosis increases. Here, we show that WD40 repeat-containing protein 6 (WDR6) promotes hepatic DNL during IR. Mechanistically, WDR6 interacts with the beta-type catalytic subunit of serine/threonine-protein phosphatase 1 (PPP1CB) to facilitate PPP1CB dephosphorylation at Thr316, which subsequently enhances fatty acid synthases transcription through DNA-dependent protein kinase and upstream stimulatory factor 1. Using molecular dynamics simulation analysis, we find a small natural compound, XLIX, that inhibits the interaction of WDR6 with PPP1CB, thus reducing DNL in IR states. Together, these results reveal WDR6 as a promising target for the treatment of hepatic steatosis.
Topics: Animals; Mice; Lipogenesis; Insulin Resistance; Up-Regulation; Fatty Liver; Insulin
PubMed: 37735236
DOI: 10.1038/s42255-023-00896-7 -
Cell Reports Jun 2023The nuclear factor κB (NF-κB) pathway plays essential roles in innate and adaptive immunity, but little is known how NF-κB signaling is compartmentalized and...
The nuclear factor κB (NF-κB) pathway plays essential roles in innate and adaptive immunity, but little is known how NF-κB signaling is compartmentalized and spatiotemporally activated in the cytoplasm. Here, we show that the lipogenesis signal cascade Scap-SREBP1-S1P/S2P orchestrates the homeostasis and spatiotemporal activation of NF-κB. SREBP cleavage-activating protein (Scap) and sterol regulatory element-binding protein 1 (SREBP1) form a super complex with inhibitors of NF-κB α (IκBα) to associate NF-κB close to the endoplasmic reticulum (ER). Upon lipopolysaccharide (LPS) stimulation, Scap transports the complex to the Golgi apparatus, where SREBP1 is cleaved by site-1 protease (S1P)/S2P, liberating IκBα for IκB kinase (Ikk)-mediated phosphorylation and subsequent activation of NF-κB. Loss of Scap or inhibition of S1P or S2P diminishes, while SREBP1 deficiency augments, LPS-induced NF-κB activation and subsequent inflammatory responses. Our results reveal the Scap-SREBP1 complex as an additional cytoplasmic checkpoint for NF-κB homeostasis and unveil the Golgi apparatus as the optimal cellular platform for NF-κB activation, providing insights into the crosstalk between lipogenesis signaling and immunity.
Topics: Homeostasis; Lipogenesis; Lipopolysaccharides; NF-kappa B; NF-KappaB Inhibitor alpha; Sterol Regulatory Element Binding Protein 1; Humans; Animals; Mice
PubMed: 37267109
DOI: 10.1016/j.celrep.2023.112586 -
Nature Genetics Oct 2023Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS)... (Meta-Analysis)
Meta-Analysis
Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Genome-Wide Association Study; Liver Cirrhosis; Acyltransferases; Phospholipases; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Liver; Protein Serine-Threonine Kinases; Intracellular Signaling Peptides and Proteins; Alpha-Ketoglutarate-Dependent Dioxygenase FTO
PubMed: 37709864
DOI: 10.1038/s41588-023-01497-6 -
Cell Metabolism Nov 2023The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the...
The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty acids were channeled toward ketogenesis in carriers, which was associated with an increase in hepatic mitochondrial redox state. During a ketogenic diet, carriers manifested increased rates of intrahepatic lipolysis, increased plasma β-hydroxybutyrate concentrations, and decreased rates of hepatic mitochondrial citrate synthase flux. These studies demonstrate that homozygous PNPLA3 I148M carriers have hepatic mitochondrial dysfunction leading to reduced DNL and channeling of carbons to ketogenesis. These findings have implications for understanding why the PNPLA3 variant predisposes to progressive liver disease.
Topics: Humans; Lipogenesis; 3-Hydroxybutyric Acid; Liver; Non-alcoholic Fatty Liver Disease; Mitochondria; Genetic Predisposition to Disease
PubMed: 37909034
DOI: 10.1016/j.cmet.2023.10.008 -
Hepatology (Baltimore, Md.) Dec 2023SLC25A47 was initially identified as a mitochondrial HCC-downregulated carrier protein, but its physiological functions and transport substrates are unknown. We aimed to...
BACKGROUND AIMS
SLC25A47 was initially identified as a mitochondrial HCC-downregulated carrier protein, but its physiological functions and transport substrates are unknown. We aimed to investigate the physiological role of SLC25A47 in hepatic metabolism.
APPROACH RESULTS
In the treatment of hepatocytes with metformin, we found that metformin can transcriptionally activate the expression of Slc25a47 , which is required for AMP-activated protein kinase α (AMPKα) phosphorylation. Slc25a47 -deficient mice had increased hepatic lipid content, triglycerides, and cholesterol levels, and we found that Slc25a47 deficiency suppressed AMPKα phosphorylation and led to an increased accumulation of nuclear SREBPs, with elevated fatty acid and cholesterol biosynthetic activities. Conversely, when Slc25a47 was overexpressed in mouse liver, AMPKα was activated and resulted in the inhibition of lipogenesis. Moreover, using a diethylnitrosamine-induced mouse HCC model, we found that the deletion of Slc25a47 promoted HCC tumorigenesis and development through the activated mammalian target of rapamycin cascade. Employing homology modeling of SLC25A47 and virtual screening of the human metabolome database, we demonstrated that NAD + was an endogenous substrate for SLC25A47, and the activity of NAD + -dependent sirtuin 3 declined in Slc25a47 -deficient mice, followed by inactivation of AMPKα.
CONCLUSIONS
Our findings reveal that SLC25A47, a hepatocyte-specific mitochondrial NAD + transporter, is one of the pharmacological targets of metformin and regulates lipid homeostasis through AMPKα, and may serve as a potential drug target for treating NAFLD and HCC.
Topics: Animals; Humans; Mice; AMP-Activated Protein Kinases; Lipid Metabolism; NAD; Carcinoma, Hepatocellular; Liver Neoplasms; Liver; Metformin; Carcinogenesis; Cell Transformation, Neoplastic; Fatty Acids; Cholesterol; Mammals
PubMed: 36804859
DOI: 10.1097/HEP.0000000000000314