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Clinical Science (London, England :... Sep 2022The metabolic-associated fatty liver disease (MAFLD) is a condition of fat accumulation in the liver in combination with metabolic dysfunction in the form of overweight... (Review)
Review
The metabolic-associated fatty liver disease (MAFLD) is a condition of fat accumulation in the liver in combination with metabolic dysfunction in the form of overweight or obesity and insulin resistance. It is also associated with an increased cardiovascular disease risk, including hypertension and atherosclerosis. Hepatic lipid metabolism is regulated by a combination of the uptake and export of fatty acids, de novo lipogenesis, and fat utilization by β-oxidation. When the balance between these pathways is altered, hepatic lipid accumulation commences, and long-term activation of inflammatory and fibrotic pathways can progress to worsen the liver disease. This review discusses the details of the molecular mechanisms regulating hepatic lipids and the emerging therapies targeting these pathways as potential future treatments for MAFLD.
Topics: Fatty Acids; Humans; Lipid Metabolism; Lipogenesis; Liver; Non-alcoholic Fatty Liver Disease; Triglycerides
PubMed: 36148775
DOI: 10.1042/CS20220572 -
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 -
British Journal of Cancer Jan 2020A common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and... (Review)
Review
A common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and survival. In particular, the importance of altered fatty acid metabolism in cancer has received renewed interest as, aside their principal role as structural components of the membrane matrix, they are important secondary messengers, and can also serve as fuel sources for energy production. In this review, we will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (1) The role of de novo synthesis and exogenous uptake in the cellular pool of fatty acids. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K-AKT-mTOR signalling, regulate fatty acid metabolism. (3) The role of fatty acids as essential mediators of cancer progression and metastasis, through remodelling of the tumour microenvironment. (4) Therapeutic strategies and considerations for successfully targeting fatty acid metabolism in cancer. Further research focusing on the complex interplay between oncogenic signalling and dysregulated fatty acid metabolism holds great promise to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.
Topics: Carcinogenesis; Epigenome; Fatty Acids; Humans; Lipogenesis; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Microenvironment
PubMed: 31819192
DOI: 10.1038/s41416-019-0650-z -
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 Communications Apr 2022Elevated de novo lipogenesis is considered to be a crucial factor in hepatocellular carcinoma (HCC) development. Herein, we identify ubiquitin-specific protease 22...
Elevated de novo lipogenesis is considered to be a crucial factor in hepatocellular carcinoma (HCC) development. Herein, we identify ubiquitin-specific protease 22 (USP22) as a key regulator for de novo fatty acid synthesis, which directly interacts with deubiquitinates and stabilizes peroxisome proliferator-activated receptor gamma (PPARγ) through K48-linked deubiquitination, and in turn, this stabilization increases acetyl-CoA carboxylase (ACC) and ATP citrate lyase (ACLY) expressions. In addition, we find that USP22 promotes de novo fatty acid synthesis and contributes to HCC tumorigenesis, however, this tumorigenicity is suppressed by inhibiting the expression of PPARγ, ACLY, or ACC in in vivo tumorigenesis experiments. In HCC, high expression of USP22 positively correlates with PPARγ, ACLY or ACC expression, and associates with a poor prognosis. Taken together, we identify a USP22-regulated lipogenesis mechanism that involves the PPARγ-ACLY/ACC axis in HCC tumorigenesis and provide a rationale for therapeutic targeting of lipogenesis via USP22 inhibition.
Topics: ATP Citrate (pro-S)-Lyase; Acetyl-CoA Carboxylase; Carcinogenesis; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Fatty Acids; Humans; Lipidomics; Lipogenesis; Liver Neoplasms; PPAR gamma; Ubiquitin Thiolesterase
PubMed: 35449157
DOI: 10.1038/s41467-022-29846-9 -
Nutrients Aug 2022The incidence of Non-Alcoholic Fatty Liver Disease (NAFLD) has been rapidly increasing during the last decade. It is a relevant health problem that affects 25% of the... (Review)
Review
The incidence of Non-Alcoholic Fatty Liver Disease (NAFLD) has been rapidly increasing during the last decade. It is a relevant health problem that affects 25% of the general population. NAFLD involves an extensive array of clinical conditions. So far, no approved pharmacological therapy for NAFLD has been developed. Multiple bioactive compounds have been proposed to treat NAFLD. One of the most promising is Berberine (BBR). Its pleiotropic effect positively impacts various cardiometabolic aspects. In this review, we summarize NAFLD, its metabolic and cardiovascular complications, the hepatoprotective effects of BBR due to its broad spectrum of pharmacological effects, and the potential role of BBR in NAFLD therapy. BBR ameliorates NAFLD by affecting numerous abnormalities. It inhibits lipogenesis and gluconeogenesis, improves insulin resistance and lipid profile, and modulates gut microbiota. The exact mechanism underlying these effects is not yet entirely explained. A growing amount of evidence confirming the positive effects of BBR on multiple metabolic pathways, such as lipids and glucose metabolism, energy homeostasis, or gut microbiota modulation, allows us to speculate about the importance of this natural bioactive substance for NAFLD therapy.
Topics: Berberine; Gluconeogenesis; Humans; Insulin Resistance; Lipogenesis; Liver; Non-alcoholic Fatty Liver Disease
PubMed: 36079717
DOI: 10.3390/nu14173459 -
Journal of Hepatology Oct 2020Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by hepatic lipid accumulation, inflammation, and progressive fibrosis. Acetyl-CoA...
BACKGROUND & AIMS
Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by hepatic lipid accumulation, inflammation, and progressive fibrosis. Acetyl-CoA carboxylase (ACC) catalyzes the rate-limiting step of de novo lipogenesis and regulates fatty acid β-oxidation in hepatocytes. ACC inhibition reduces hepatic fat content and markers of liver injury in patients with NASH; however, the effect of ACC inhibition on liver fibrosis has not been reported.
METHODS
A direct role for ACC in fibrosis was evaluated by measuring de novo lipogenesis, procollagen production, gene expression, glycolysis, and mitochondrial respiration in hepatic stellate cells (HSCs) in the absence or presence of small molecule inhibitors of ACC. ACC inhibitors were evaluated in rodent models of liver fibrosis induced by diet or the hepatotoxin, diethylnitrosamine. Fibrosis and hepatic steatosis were evaluated by histological and biochemical assessments.
RESULTS
Inhibition of ACC reduced the activation of TGF-β-stimulated HSCs, as measured by both α-SMA expression and collagen production. ACC inhibition prevented a metabolic switch necessary for induction of glycolysis and oxidative phosphorylation during HSC activation. While the molecular mechanism by which inhibition of de novo lipogenesis blocks glycolysis and oxidative phosphorylation is unknown, we definitively show that HSCs require de novo lipogenesis for activation. Consistent with this direct antifibrotic mechanism in HSCs, ACC inhibition reduced liver fibrosis in a rat choline-deficient, high-fat diet model and in response to chronic diethylnitrosamine-induced liver injury (in the absence of hepatic lipid accumulation).
CONCLUSIONS
In addition to reducing lipid accumulation in hepatocytes, ACC inhibition also directly impairs the profibrogenic activity of HSCs. Thus, small molecule inhibitors of ACC may lessen fibrosis by reducing lipotoxicity in hepatocytes and by preventing HSC activation, providing a mechanistic rationale for the treatment of patients with advanced liver fibrosis due to NASH.
LAY SUMMARY
Hepatic fibrosis is the most important predictor of liver-related outcomes in patients with non-alcoholic steatohepatitis (NASH). Small molecule inhibitors of acetyl-CoA carboxylase (ACC) reduce hepatic fat content and markers of liver injury in patients with NASH. Herein, we report that inhibition of ACC and de novo lipogenesis also directly suppress the activation of hepatic stellate cells - the primary cell responsible for generating fibrotic scar in the liver - and thus fibrosis. These data provide further evidence for the use of ACC inhibitors to treat patients with NASH and advanced fibrosis.
Topics: Acetyl-CoA Carboxylase; Animals; Biomarkers; Cell Line; Diet, High-Fat; Disease Models, Animal; Hepatic Stellate Cells; Humans; Lipogenesis; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Rats; Rats, Wistar
PubMed: 32376414
DOI: 10.1016/j.jhep.2020.04.037 -
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