-
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 -
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. 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 -
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 -
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 -
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 -
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 -
Biological Reviews of the Cambridge... May 2016Hepatic de novo lipogenesis (DNL) is the biochemical process of synthesising fatty acids from acetyl-CoA subunits that are produced from a number of different pathways... (Review)
Review
Hepatic de novo lipogenesis (DNL) is the biochemical process of synthesising fatty acids from acetyl-CoA subunits that are produced from a number of different pathways within the cell, most commonly carbohydrate catabolism. In addition to glucose which most commonly supplies carbon units for DNL, fructose is also a profoundly lipogenic substrate that can drive DNL, important when considering the increasing use of fructose in corn syrup as a sweetener. In the context of disease, DNL is thought to contribute to the pathogenesis of non-alcoholic fatty liver disease, a common condition often associated with the metabolic syndrome and consequent insulin resistance. Whether DNL plays a significant role in the pathogenesis of insulin resistance is yet to be fully elucidated, but it may be that the prevalent products of this synthetic process induce some aspect of hepatic insulin resistance.
Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Glucose; Humans; Lipogenesis; Liver Diseases; Prediabetic State
PubMed: 25740151
DOI: 10.1111/brv.12178 -
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 -
Journal of Hepatology Jul 2021Excessive fructose intake is associated with increased de novo lipogenesis, blood triglycerides, and hepatic insulin resistance. We aimed to determine whether fructose... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
Excessive fructose intake is associated with increased de novo lipogenesis, blood triglycerides, and hepatic insulin resistance. We aimed to determine whether fructose elicits specific effects on lipid metabolism independently of excessive caloric intake.
METHODS
A total of 94 healthy men were studied in this double-blind, randomized trial. They were assigned to daily consumption of sugar-sweetened beverages (SSBs) containing moderate amounts of fructose, sucrose (fructose-glucose disaccharide) or glucose (80 g/day) in addition to their usual diet or SSB abstinence (control group) for 7 weeks. De novo fatty acid (FA) and triglyceride synthesis, lipolysis and plasma free FA (FFA) oxidation were assessed by tracer methodology.
RESULTS
Daily intake of beverages sweetened with free fructose and fructose combined with glucose (sucrose) led to a 2-fold increase in basal hepatic fractional secretion rates (FSR) compared to control (median FSR %/day: sucrose 20.8 (p = 0.0015); fructose 19.7 (p = 0.013); control 9.1). Conversely, the same amounts of glucose did not change FSR (median of FSR %/day 11.0 (n.s.)). Fructose intake did not change basal secretion of newly synthesized VLDL-triglyceride, nor did it alter rates of peripheral lipolysis, nor total FA and plasma FFA oxidation. Total energy intake was similar across groups.
CONCLUSIONS
Regular consumption of both fructose- and sucrose-sweetened beverages in moderate doses - associated with stable caloric intake - increases hepatic FA synthesis even in a basal state; this effect is not observed after glucose consumption. These findings provide evidence of an adaptative response to regular fructose exposure in the liver.
LAY SUMMARY
This study investigated the metabolic effects of daily sugar-sweetened beverage consumption for several weeks in healthy lean men. It revealed that beverages sweetened with the sugars fructose and sucrose (glucose and fructose combined), but not glucose, increase the ability of the liver to produce lipids. This change may pave the way for further unfavorable effects on metabolic health.
CLINICAL TRIAL REGISTRATION NUMBER
NCT01733563.
Topics: Adult; Double-Blind Method; Energy Intake; Fatty Acids; Fructose; Glucose; Healthy Volunteers; Humans; Lipid Metabolism; Lipogenesis; Lipoproteins, VLDL; Liver; Male; Sucrose; Sugar-Sweetened Beverages; Sweetening Agents; Triglycerides
PubMed: 33684506
DOI: 10.1016/j.jhep.2021.02.027