-
Nature Metabolism May 2023Lipids are essential metabolites, which function as energy sources, structural components and signalling mediators. Most cells are able to convert carbohydrates into... (Review)
Review
Lipids are essential metabolites, which function as energy sources, structural components and signalling mediators. Most cells are able to convert carbohydrates into fatty acids, which are often converted into neutral lipids for storage in the form of lipid droplets. Accumulating evidence suggests that lipogenesis plays a crucial role not only in metabolic tissues for systemic energy homoeostasis but also in immune and nervous systems for their proliferation, differentiation and even pathophysiological roles. Thus, excessive or insufficient lipogenesis is closely associated with aberrations in lipid homoeostasis, potentially leading to pathological consequences, such as dyslipidaemia, diabetes, fatty liver, autoimmune diseases, neurodegenerative diseases and cancers. For systemic energy homoeostasis, multiple enzymes involved in lipogenesis are tightly controlled by transcriptional and post-translational modifications. In this Review, we discuss recent findings regarding the regulatory mechanisms, physiological roles and pathological importance of lipogenesis in multiple tissues such as adipose tissue and the liver, as well as the immune and nervous systems. Furthermore, we briefly introduce the therapeutic implications of lipogenesis modulation.
Topics: Humans; Lipogenesis; Adipose Tissue; Fatty Acids; Fatty Liver
PubMed: 37142787
DOI: 10.1038/s42255-023-00786-y -
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 -
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 -
The Journal of Endocrinology May 2023Despite the existence of numerous studies supporting a pathological link between fructose consumption and the development of the metabolic syndrome and its sequelae,... (Review)
Review
Despite the existence of numerous studies supporting a pathological link between fructose consumption and the development of the metabolic syndrome and its sequelae, such as non-alcoholic fatty liver disease (NAFLD), this link remains a contentious issue. With this article, we shed a light on the impact of sugar/fructose intake on hepatic de novo lipogenesis (DNL), an outcome parameter known to be dysregulated in subjects with type 2 diabetes and/or NAFLD. In this review, we present findings from human intervention studies using physiological doses of sugar as well as mechanistic animal studies. There is evidence from both human and animal studies that fructose is a more potent inducer of hepatic lipogenesis than glucose. This is most likely due to the liver's prominent physiological role in fructose metabolism, which may be disrupted under pathological conditions by increased hepatic expression of fructolytic and lipogenic enzymes. Increased DNL may not only contribute to ectopic fat deposition (i.e. in the liver), but it may also impair several metabolic processes through DNL-related fatty acids (e.g. beta-cell function, insulin secretion, or insulin sensitivity).
Topics: Animals; Humans; Non-alcoholic Fatty Liver Disease; Fructose; Lipogenesis; Diabetes Mellitus, Type 2; Liver
PubMed: 36753292
DOI: 10.1530/JOE-22-0270 -
Current Opinion in Clinical Nutrition... Jul 2019To review recent evidence for the role of carbohydrates in the promotion of de novo lipogenesis and lipoprotein secretion from the intestine. (Review)
Review
PURPOSE OF REVIEW
To review recent evidence for the role of carbohydrates in the promotion of de novo lipogenesis and lipoprotein secretion from the intestine.
RECENT FINDINGS
The consumption of diets rich in carbohydrates have been shown to promote elevations in circulating lipids. In particular, the consumption of monosaccharides, such as glucose and fructose, have been shown to induce increases in intestinal de novo lipogenesis, as well as be used as a substrate for the synthesis of triglycerides and lipoprotein export in the form of chylomicrons. Recently, various systematic reviews have analyzed the relative contribution of dietary fructose to intestinal lipogenesis. Although, there remains controversy within the literature, the body of evidence supports lipogenic effects of high fructose diets. In addition, alterations in markers of de novo lipogenesis within the jejunum of patients with insulin resistance may explain the alterations in their postprandial lipid profile.
SUMMARY
Recent evidence supports the contribution of dietary carbohydrates to intestinal lipogenesis and lipoprotein secretion; however, further research is required to fully understand the mechanisms underlying this complex process.
Topics: Chylomicrons; Dietary Carbohydrates; Fructose; Humans; Intestinal Mucosa; Intestines; Lipogenesis; Triglycerides
PubMed: 31107259
DOI: 10.1097/MCO.0000000000000569 -
MIGA2 Links Mitochondria, the ER, and Lipid Droplets and Promotes De Novo Lipogenesis in Adipocytes.Molecular Cell Dec 2019Physical contact between organelles is vital to the function of eukaryotic cells. Lipid droplets (LDs) are dynamic organelles specialized in lipid storage that interact...
Physical contact between organelles is vital to the function of eukaryotic cells. Lipid droplets (LDs) are dynamic organelles specialized in lipid storage that interact physically with mitochondria in several cell types. The mechanisms coupling these organelles are, however, poorly understood, and the cell-biological function of their interaction remains largely unknown. Here, we discover in adipocytes that the outer mitochondrial membrane protein MIGA2 links mitochondria to LDs. We identify an amphipathic LD-targeting motif and reveal that MIGA2 binds to the membrane proteins VAP-A or VAP-B in the endoplasmic reticulum (ER). We find that in adipocytes MIGA2 is involved in promoting triglyceride (TAG) synthesis from non-lipid precursors. Our data indicate that MIGA2 links reactions of de novo lipogenesis in mitochondria to TAG production in the ER, thereby facilitating efficient lipid storage in LDs. Based on its presence in many tissues, MIGA2 is likely critical for lipid and energy homeostasis in a wide spectrum of cell types.
Topics: 3T3 Cells; Adipocytes; Animals; COS Cells; Cell Differentiation; Chlorocebus aethiops; Endoplasmic Reticulum; HEK293 Cells; Humans; Lipid Droplets; Lipogenesis; Membrane Proteins; Mice; Mitochondria; Mitochondrial Proteins; Triglycerides; Vesicular Transport Proteins
PubMed: 31628041
DOI: 10.1016/j.molcel.2019.09.011 -
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 Hepatology Feb 2024The hepatic accumulation of excess triglycerides is a seminal event in the initiation and progression of non-alcoholic fatty liver disease (NAFLD). Hepatic steatosis... (Review)
Review
The hepatic accumulation of excess triglycerides is a seminal event in the initiation and progression of non-alcoholic fatty liver disease (NAFLD). Hepatic steatosis occurs when the hepatic accrual of fatty acids from the plasma and de novo lipogenesis (DNL) is no longer balanced by rates of fatty acid oxidation and secretion of very low-density lipoprotein-triglycerides. Accumulating data indicate that increased rates of DNL are central to the development of hepatic steatosis in NAFLD. Whereas the main drivers in NAFLD are transcriptional, owing to both hyperinsulinemia and hyperglycaemia, the effectors of DNL are a series of well-characterised enzymes. Several have proven amenable to pharmacologic inhibition or oligonucleotide-mediated knockdown, with lead compounds showing liver fat-lowering efficacy in phase II clinical trials. In humans with NAFLD, percent reductions in liver fat have closely mirrored percent inhibition of DNL, thereby affirming the critical contributions of DNL to NAFLD pathogenesis. The safety profiles of these compounds have so far been encouraging. It is anticipated that inhibitors of DNL, when administered alone or in combination with other therapeutic agents, will become important agents in the management of human NAFLD.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Lipogenesis; Liver; Lipid Metabolism; Triglycerides
PubMed: 37977245
DOI: 10.1016/j.jhep.2023.10.042 -
Diabetes Apr 2020Hepatosteatosis, which is frequently associated with development of metabolic syndrome and insulin resistance, manifests when triglyceride (TG) input in the liver is... (Review)
Review
Hepatosteatosis, which is frequently associated with development of metabolic syndrome and insulin resistance, manifests when triglyceride (TG) input in the liver is greater than TG output, resulting in the excess accumulation of TG. Dysregulation of lipogenesis therefore has the potential to increase lipid accumulation in the liver, leading to insulin resistance and type 2 diabetes. Recently, efforts have been made to examine the epigenetic regulation of metabolism by histone-modifying enzymes that alter chromatin accessibility for activation or repression of transcription. For regulation of lipogenic gene transcription, various known lipogenic transcription factors, such as USF1, ChREBP, and LXR, interact with and recruit specific histone modifiers, directing specificity toward lipogenesis. Alteration or impairment of the functions of these histone modifiers can lead to dysregulation of lipogenesis and thus hepatosteatosis leading to insulin resistance and type 2 diabetes.
Topics: Animals; Diabetes Mellitus; Epigenesis, Genetic; Fatty Liver; Humans; Insulin Resistance; Lipogenesis; Liver; Metabolic Syndrome
PubMed: 32198196
DOI: 10.2337/dbi18-0032 -
International Journal of Environmental... Mar 2021In recent years, lipid metabolism has gained greater attention in several diseases including cancer. Dysregulation of fatty acid metabolism is a key component in breast... (Review)
Review
In recent years, lipid metabolism has gained greater attention in several diseases including cancer. Dysregulation of fatty acid metabolism is a key component in breast cancer malignant transformation. In particular, de novo lipogenesis provides the substrate required by the proliferating tumor cells to maintain their membrane composition and energetic functions during enhanced growth. However, it appears that not all breast cancer subtypes depend on de novo lipogenesis for fatty acid replenishment. Indeed, while breast cancer luminal subtypes rely on de novo lipogenesis, the basal-like receptor-negative subtype overexpresses genes involved in the utilization of exogenous-derived fatty acids, in the synthesis of triacylglycerols and lipid droplets, and fatty acid oxidation. These metabolic differences are specifically associated with genomic and proteomic changes that can perturb lipogenic enzymes and related pathways. This behavior is further supported by the observation that breast cancer patients can be stratified according to their molecular profiles. Moreover, the discovery that extracellular vesicles act as a vehicle of metabolic enzymes and oncometabolites may provide the opportunity to noninvasively define tumor metabolic signature. Here, we focus on de novo lipogenesis and the specific differences exhibited by breast cancer subtypes and examine the functional contribution of lipogenic enzymes and associated transcription factors in the regulation of tumorigenic processes.
Topics: Breast Neoplasms; Fatty Acids; Humans; Lipid Metabolism; Lipogenesis; Proteomics
PubMed: 33808259
DOI: 10.3390/ijerph18073575