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Comprehensive Physiology Dec 2017Triglyceride molecules represent the major form of storage and transport of fatty acids within cells and in the plasma. The liver is the central organ for fatty acid... (Review)
Review
Triglyceride molecules represent the major form of storage and transport of fatty acids within cells and in the plasma. The liver is the central organ for fatty acid metabolism. Fatty acids accrue in liver by hepatocellular uptake from the plasma and by de novo biosynthesis. Fatty acids are eliminated by oxidation within the cell or by secretion into the plasma within triglyceride-rich very low-density lipoproteins. Notwithstanding high fluxes through these pathways, under normal circumstances the liver stores only small amounts of fatty acids as triglycerides. In the setting of overnutrition and obesity, hepatic fatty acid metabolism is altered, commonly leading to the accumulation of triglycerides within hepatocytes, and to a clinical condition known as nonalcoholic fatty liver disease (NAFLD). In this review, we describe the current understanding of fatty acid and triglyceride metabolism in the liver and its regulation in health and disease, identifying potential directions for future research. Advances in understanding the molecular mechanisms underlying the hepatic fat accumulation are critical to the development of targeted therapies for NAFLD. © 2018 American Physiological Society. Compr Physiol 8:1-22, 2018.
Topics: Biological Transport; Fatty Acids; Humans; Lipid Metabolism; Lipogenesis; Lipolysis; Liver; Non-alcoholic Fatty Liver Disease; Triglycerides
PubMed: 29357123
DOI: 10.1002/cphy.c170012 -
Cancer Communications (London, England) May 2018Reprogramming of lipid metabolism is a newly recognized hallmark of malignancy. Increased lipid uptake, storage and lipogenesis occur in a variety of cancers and... (Review)
Review
Reprogramming of lipid metabolism is a newly recognized hallmark of malignancy. Increased lipid uptake, storage and lipogenesis occur in a variety of cancers and contribute to rapid tumor growth. Lipids constitute the basic structure of membranes and also function as signaling molecules and energy sources. Sterol regulatory element-binding proteins (SREBPs), a family of membrane-bound transcription factors in the endoplasmic reticulum, play a central role in the regulation of lipid metabolism. Recent studies have revealed that SREBPs are highly up-regulated in various cancers and promote tumor growth. SREBP cleavage-activating protein is a key transporter in the trafficking and activation of SREBPs as well as a critical glucose sensor, thus linking glucose metabolism and de novo lipid synthesis. Targeting altered lipid metabolic pathways has become a promising anti-cancer strategy. This review summarizes recent progress in our understanding of lipid metabolism regulation in malignancy, and highlights potential molecular targets and their inhibitors for cancer treatment.
Topics: Animals; Antineoplastic Agents; Endoplasmic Reticulum; Humans; Intracellular Signaling Peptides and Proteins; Lipid Metabolism; Lipogenesis; Membrane Proteins; Models, Biological; Neoplasms; Sterol Regulatory Element Binding Proteins
PubMed: 29784041
DOI: 10.1186/s40880-018-0301-4 -
International Journal of Molecular... Apr 2021Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of non-alcoholic fatty liver disease... (Review)
Review
Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD). Metabolic dysfunction in this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome, with insulin resistance as the common underlying pathophysiology. Imbalance between energy intake and expenditure results in insulin resistance in various tissues and alteration of the gut microbiota, resulting in fat accumulation in the liver. The role of genetics has also been revealed in hepatic fat accumulation and fibrosis. In the process of fat accumulation in the liver, intracellular damage as well as hepatic insulin resistance further potentiates inflammation, fibrosis, and carcinogenesis. Increased lipogenic substrate supply from other tissues, hepatic zonation of Irs1, and other factors, including ER stress, play crucial roles in increased hepatic de novo lipogenesis in MAFLD with hepatic insulin resistance. Herein, we provide an overview of the factors contributing to and the role of systemic and local insulin resistance in the development and progression of MAFLD.
Topics: Animals; Humans; Insulin; Lipogenesis; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Signal Transduction
PubMed: 33923817
DOI: 10.3390/ijms22084156 -
Journal of Lipid Research Apr 2020Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease with significant morbidity and mortality worldwide. ALD begins with simple hepatic... (Review)
Review
Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease with significant morbidity and mortality worldwide. ALD begins with simple hepatic steatosis and progresses to alcoholic steatohepatitis, fibrosis, and cirrhosis. The severity of hepatic steatosis is highly associated with the development of later stages of ALD. This review explores the disturbances of alcohol-induced hepatic lipid metabolism through altered hepatic lipid uptake, de novo lipid synthesis, fatty acid oxidation, hepatic lipid export, and lipid droplet formation and catabolism. In addition, we review emerging data on the contributions of genetics and bioactive lipid metabolism in alcohol-induced hepatic lipid accumulation.
Topics: Animals; Ethanol; Humans; Lipid Metabolism; Lipogenesis; Liver
PubMed: 32029510
DOI: 10.1194/jlr.R119000547 -
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 -
Nature Reviews. Drug Discovery Apr 2022Fatty acids are essential for survival, acting as bioenergetic substrates, structural components and signalling molecules. Given their vital role, cells have evolved... (Review)
Review
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 acids from alternative carbon sources, through a process known as de novo lipogenesis (DNL). Despite the importance of DNL, aberrant upregulation is associated with a wide variety of pathologies. Inhibiting core enzymes of DNL, including citrate/isocitrate carrier (CIC), ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), represents an attractive therapeutic strategy. Despite challenges related to efficacy, selectivity and safety, several new classes of synthetic DNL inhibitors have entered clinical-stage development and may become the foundation for a new class of therapeutics.
Topics: ATP Citrate (pro-S)-Lyase; Acetyl-CoA Carboxylase; Fatty Acids; Humans; Lipogenesis; Signal Transduction
PubMed: 35031766
DOI: 10.1038/s41573-021-00367-2 -
Nature Reviews. Molecular Cell Biology Nov 2015Fatty acid and fat synthesis in the liver is a highly regulated metabolic pathway that is important for very low-density lipoprotein (VLDL) production and thus energy... (Review)
Review
Fatty acid and fat synthesis in the liver is a highly regulated metabolic pathway that is important for very low-density lipoprotein (VLDL) production and thus energy distribution to other tissues. Having common features at their promoter regions, lipogenic genes are coordinately regulated at the transcriptional level. Transcription factors, such as upstream stimulatory factors (USFs), sterol regulatory element-binding protein 1C (SREBP1C), liver X receptors (LXRs) and carbohydrate-responsive element-binding protein (ChREBP) have crucial roles in this process. Recently, insights have been gained into the signalling pathways that regulate these transcription factors. After feeding, high blood glucose and insulin levels activate lipogenic genes through several pathways, including the DNA-dependent protein kinase (DNA-PK), atypical protein kinase C (aPKC) and AKT-mTOR pathways. These pathways control the post-translational modifications of transcription factors and co-regulators, such as phosphorylation, acetylation or ubiquitylation, that affect their function, stability and/or localization. Dysregulation of lipogenesis can contribute to hepatosteatosis, which is associated with obesity and insulin resistance.
Topics: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; DNA-Activated Protein Kinase; Fatty Acids; Gene Expression Regulation; Lipogenesis; Lipoproteins, VLDL; Liver; Liver X Receptors; Mice; Nuclear Proteins; Orphan Nuclear Receptors; Protein Kinase C; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Signal Transduction; Sterol Regulatory Element Binding Protein 1; TOR Serine-Threonine Kinases; Transcription Factors; Transcription, Genetic; Upstream Stimulatory Factors
PubMed: 26490400
DOI: 10.1038/nrm4074 -
Molecular Medicine (Cambridge, Mass.) Jun 2019Non-alcoholic fatty liver disease (NAFLD) is a common hepatic disease with an increasing prevalence but an unclear aetiology. This study aimed to investigate the...
BACKGROUND
Non-alcoholic fatty liver disease (NAFLD) is a common hepatic disease with an increasing prevalence but an unclear aetiology. This study aimed to investigate the functional implications of microRNA-122 (miR-122) in the pathogenesis of NAFLD and the possible molecular mechanisms.
METHODS
Both in vitro and in vivo models of NAFLD were generated by treating HepG2 and Huh-7 cells with free fatty acids (FFA) and by feeding mice a high-fat diet (HFD), respectively. HE and Oil Red O staining were used to examine liver tissue morphology and lipid deposition, respectively. Immunohistochemical (IHC) staining was used to examine Sirt1 expression in liver tissues. qRT-PCR and Western blotting were employed to measure the expression of miR-122, Sirt1, and proteins involved in lipogenesis and the AMPK pathway. Enzyme-linked immunosorbent assay (ELISA) was used to quantify triglyceride (TG) levels in HepG2 and Huh-7 cells and in liver tissues. The interaction between miR-122 and the Sirt1 gene was further examined by a dual luciferase reporter assay and RNA-immunoprecipitation (RIP).
RESULTS
NAFLD hepatic tissues and FFA-treated HepG2 and Huh-7 cells presented excess lipid production and TG secretion, accompanied by miR-122 upregulation, Sirt1 downregulation, and potentiated lipogenesis-related genes. miR-122 suppressed Sirt1 expression via binding to its 3'-untranslated region (UTR). Knockdown of miR-122 effectively mitigated excessive lipid production and suppressed the expression of lipogenic genes in FFA-treated HepG2 and Huh-7 cells via upregulating Sirt1. Furthermore, miR-122 knockdown activated the LKB1/AMPK signalling pathway.
CONCLUSION
The inhibition of miR-122 protects hepatocytes from lipid metabolic disorders such as NAFLD and suppresses lipogenesis via elevating Sirt1 and activating the AMPK pathway. These data support miR-122 as a promising biomarker and drug target for NAFLD.
Topics: AMP-Activated Protein Kinases; Cell Line, Tumor; Enzyme-Linked Immunosorbent Assay; Hep G2 Cells; Humans; Immunohistochemistry; Lipid Metabolism; Lipogenesis; Liver; MicroRNAs; Non-alcoholic Fatty Liver Disease; Signal Transduction; Sirtuin 1
PubMed: 31195981
DOI: 10.1186/s10020-019-0085-2 -
Molecular Therapy : the Journal of the... Jun 2022Type 2 diabetes mellitus (DM2) is associated closely with non-alcoholic fatty liver disease (NAFLD) by affecting lipid metabolism, which may lead to non-alcoholic...
Type 2 diabetes mellitus (DM2) is associated closely with non-alcoholic fatty liver disease (NAFLD) by affecting lipid metabolism, which may lead to non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). N-methyladenosine (m6A) RNA methylation is an important epigenetic regulation for gene expression and is related to HCC development. We developed a new NAFLD model oriented from DM2 mouse, which spontaneously progressed to histological features of NASH, fibrosis, and HCC with high incidence. By RNA sequencing, protein expression and methylated RNA immunoprecipitation (MeRIP)-qPCR analysis, we found that enhanced expression of ACLY and SCD1 in this NAFLD model and human HCC samples was due to excessive m6A modification, but not elevation of mature SREBP1. Moreover, targeting METTL3/14 in vitro increases protein level of ACLY and SCD1 as well as triglyceride and cholesterol production and accumulation of lipid droplets. m6A sequencing analysis revealed that overexpressed METTL14 binds to mRNA of ACLY and SCD1 and alters their expression pattern. Our findings demonstrate a new NAFLD mouse model that provides a study platform for DM2-related NAFLD and reveals a unique epitranscriptional regulating mechanism for lipid metabolism via m6A-modified protein expression of ACLY and SCD1.
Topics: Animals; Carcinoma, Hepatocellular; Diabetes Mellitus, Type 2; Epigenesis, Genetic; Fibrosis; Lipogenesis; Liver Neoplasms; Mice; Non-alcoholic Fatty Liver Disease; RNA, Messenger
PubMed: 35192934
DOI: 10.1016/j.ymthe.2022.02.021 -
Trends in Endocrinology and Metabolism:... Jul 2017During insulin-resistant states such as type 2 diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production but promotes lipid synthesis leading to... (Review)
Review
During insulin-resistant states such as type 2 diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production but promotes lipid synthesis leading to hyperglycemia and hypertriglyceridemia. Defining the downstream signaling pathways underlying the control of hepatic metabolism by insulin is necessary for understanding both normal physiology and the pathogenesis of metabolic disease. We summarize recent literature highlighting the importance of both hepatic and extrahepatic mechanisms in insulin regulation of liver glucose and lipid metabolism. We posit that a failure of insulin to inappropriately regulate liver metabolism during T2DM is not exclusively from an inherent defect in canonical liver insulin signaling but is instead due to a combination of hyperinsulinemia, altered substrate supply, and the input of several extrahepatic signals.
Topics: Animals; Carbohydrate Metabolism; Glucose; Humans; Insulin; Insulin Resistance; Lipid Metabolism; Lipogenesis; Liver; Metabolic Networks and Pathways
PubMed: 28416361
DOI: 10.1016/j.tem.2017.03.003