Acly and metabolic diseases

NASH Nonalcoholic fatty liver

*

Nonalcoholic steatohepatitis （NASH） Also known as metabolic steatohepatitis , It is a clinical syndrome with pathological changes similar to alcoholic hepatitis but no history of excessive drinking , It tends to occur in middle-aged people, especially overweight and obese individuals . Nonalcoholic steatohepatitis and obesity 、 Insulin resistance 、2 Type 2 diabetes mellitus 、 Hyperlipidemia and other metabolic disorders are closely related , Its main feature is liver cell bullous steatosis with liver cell injury and inflammation , Severe cases can develop cirrhosis , There is no special treatment .

*

2022 year 6 month 7 Japan ,Cell Metabolism The magazine published online the title Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia The article . It is reported that whether it is genetics, the ATP- Specific knockout of citrate lyase ; It's still the use of the United States in pharmacology FDA Newly approved drugs ,bempedoic acid( Temporarily translated as beperdolic Acid ), Yes ATP- Citric acid lyase is inhibited ; Can make nonalcoholic fatty liver / The symptoms of inflammation were significantly relieved , At the same time, it can also reduce the cholesterol and triglyceride levels in the liver and blood (35675800).

*

ATP- Citric acid lyase （ English ：ATP citrate lyase, Also directly referred to as citrate lyase ） It is an enzyme that catalyzes important steps in fatty acid biosynthesis . This step occurs in fatty acid synthesis , Because ATP- Citrate lyase is a sugar metabolism （ capacity ） And the production of fatty acids .

*

「ACLY Participate in fatty acid formation , And in NASH Is an important target in the treatment of ！」

ACLY As a target of anticancer drugs and anti dyslipidemia and liver steatosis

ATP- Citrate lyase (ACLY) It is a central metabolic enzyme , Catalyze citric acid and coenzyme A (CoA) To oxaloacetic acid and acetyl coenzyme a Of ATP Dependency transformation . Acetyl coenzyme a Metabolism of products to fatty acids 、 The biosynthesis of cholesterol and the acetylation and isoprene of protein are very important .ACLY As a target of anticancer drugs, it has attracted considerable interest , Because many cancer cells depend on its proliferative activity .ACLY It is also the target of anti dyslipidemia and liver steatosis , Its compounds are currently in 3 In the phase of clinical trial .

*

Acetyl coenzyme A It is an important chemical substance in human body . First , Oxidative decarboxylation of pyruvate , Fatty acid β- Products of oxidation . meanwhile , It is fatty acid synthesis , Carbon source of cholesterol synthesis and ketone formation . The complete oxidation of the three nutrients leads to the same goal , Will produce acetyl coenzyme A To enter the tricarboxylic acid cycle .

*

NREP adopt ACLY Regulate liver acetyl coenzyme A And cholesterol synthesis

Liver specific insulin receptor knockout (LIRKO) Mice , This is a unique non diabetes model , Show 3 Features : High blood sugar 、 Insulin resistance and dyslipidemia , this 3 Three features endow NAFLD High risk of development . Epigenetic recombination of parental metabolic syndrome is reported TGF-β Family members , Including proteins related to neuronal regeneration (NREP) And growth differentiation factors 15 (GDF15).NREP and GDF15 Regulate the expression of several genes involved in the regulation of liver lipid metabolism . especially ,NREP Down to TGF-β Recipient /PI3K/ protein kinase B The ways of dependence have increased 3- hydroxyl -3- Methylglutaryl coenzyme a Reductase (HMGCR) and ATP- Citrate lyase (ACLY) Protein abundance , Thus regulating liver acetyl coenzyme a And cholesterol .NAFLD Patient's liver NREP The expression is reduced , Low serum NREP There is a substantial correlation between levels and steatosis and nonalcoholic steatohepatitis , indicate ACLY And NAFLD Progress related .(32250344)

Hrd1 Mediated ACLY Ubiquitination alleviates db/db Mice NAFLD

Experimental findings on diabetes mice ,Hrd1 Endoplasmic reticulum related degradation （ERAD） A subunit of the complex , And Acly Interact and ubiquitinate , So as to reduce its protein level .Hrd1 adopt Acly Pathway dependent inhibition of acetyl coenzyme A Level and inhibit fat production . stay db/db In mice and isolated mouse primary hepatocytes , The liver Hrd1 Expression and NAFLD There is a negative correlation , and Hrd1 Overexpression of improves liver steatosis and enhances insulin sensitivity .（32888949）

ACLY Expression analysis in diabetes model

GSEA The analysis shows that ACLY Low expression of , Enriched to glycine, serine and threonine metabolism 、 Drug metabolism 、 Cytochrome P450 (CYP) and NOD Like receptors (NLR) Signal path . Bioinformatics analysis shows ACLY And its related pathways may be the target of the molecular mechanism of type 2 diabetes .（31088900）

ACLY Participate in epigenetic regulation of inflammatory gene expression

Metabonomics 、 Epigenetic and transcriptomic analysis will 「GLUT3 With mitochondrial glucose oxidation and ACLY Dependent acetyl coenzyme a Generation is linked , As the speed limiting step of epigenetic regulation of inflammatory gene expression 」 . Besides , Inhibition GLUT3 Dependent acetyl coenzyme a The generation of is mitigation Th17 A promising metabolic checkpoint for cell-mediated inflammatory diseases .（35316657）

Maladjusted m6A Modification promotes adipogenesis and the development of nonalcoholic fatty liver disease and hepatocellular carcinoma

The research passed RNA Sequence 、 Protein expression and methylation RNA Immunoprecipitation （MeRIP）-qPCR analysis , Find out NAFLD Model and human liver cancer samples ACLY and SCD1 The increased expression of is due to m6A Over embellish , Not mature SREBP1 The rise of . Besides , In vitro targeting METTL3/14 Can increase the ACLY and SCD1 Protein levels as well as triglyceride and cholesterol production and lipid droplet accumulation .m6A Sequencing analysis showed , Overexpressed METTL14 And ACLY and SCD1 Of mRNA combination , And change its expression pattern .（35192934）

*

N6-methyladenosine Also called 「m6A, Is a widely existing in mRNA Base modification behavior on 」,mRNA The interior decoration of is used to maintain mRNA The stability of .
mRNA The most common interior decorations include N6- Adenylate methylation （m6A）、N1- Adenylate methylation （m1A）、 Cytosine hydroxylation （m5C） etc. .N6- Methyladenine (m6A) stay mRNA The proportion of internal modified bases is the largest , Mainly distributed in G(m6A)C (70%) perhaps A(m6A)C (30%) Conservative sequence .

*

m6A reader HNRNPA2B1 By raising ACLY and ACC1 Promote esophageal cancer