The Mechanism Of Fatty Liver In Hormone Sensitive Lipase(HSL) Deficient Mice

In animal husbandry,if a sow has fatty liver,it will seriously affect the health of her offspring,in medicine,fatty liver is a major complication of obesity and type 2 diabetes.It carries a high risk of cirrhosis and liver cancer in humans.The main cause of fatty liver is the massive accumulation of triglycerides in the cytoplasm of liver cells.Studies have shown that the catabolism of TG is involved in the formation of hepatic steatosis.The decomposition reaction of TG has been deeply studied in adipocytes.In adipocytes,the lipolysis process is divided into three steps and each step is catalyzed by a different enzyme.In the second step,the diglyceride is hydrolyzed to monoglyceride,which can be decomposed by hormone-sensitive lipase(HSL).Present studies have proved that patients with genetic defects in HSL have fatty liver.In order to explore the underlying mechanism of fatty liver fatty lesions caused by HSL deficiency,this topic made liver and adipose tissue-specific HSL knockout mice,used three HSL-knockout mouse models: systemic HSL-knockout mice(HSLSKO),liver tissue specific HSL-knockout mice(HSLLKO),and adipose tissue specific HSL-knockout mice(HSLAKO).The following results were obtained by studying the phenotypes and mechanisms of these three mice:(1)HSLSKO mice have age-dependent hepatic steatosis.By comparing body weight,liver weight,and liver triglyceride content in 3-month-old and 8-month-old HSLSKO mice with control mice,the results showed that the body weight,liver weight,and liver triglyceride content of HSLLKO mice at the age of 3-month-old had no significant differences compared with the control mice.At the age of 8 months,the body weight of HSLLKO mice was significantly lower than that of the control mice,while the liver weight and liver triglyceride content were significantly higher than those of the control mice.Besides,H & E histological staining confirmed liver steatosis in 8-month-old HSLSKO mice,indicating that hepatic steatosis in HSLSKO mice showed an age-dependent pattern.(2)HSLLKO mice did not develop hepatic steatosis.By comparing body weight,liver weight,and liver triglyceride content in 3-month-old and 8-month-old HSLLKO mice with control mice,the results showed that both 3-month-old and 8-month-old HSLLKO mice have no significant differences in body weight,liver weight,and liver triglyceride content compared with control mice.H & E histological staining confirmed that steatosis did not occur in the liver of 8-month-old HSLLKO mice.This indicated that the deficiency of liver HSL did not cause steatosis in mouse liver tissues,and the cause of hepatic steatosis in HSLLKO is in other tissues.(3)HSLAKO mice have age-dependent hepatic steatosis.By comparing body weight,liver weight,and liver triglyceride content in 3-month-old and 8-month-old HSLAKO mice with control mice,there was no significant differences in body weight,liver weight and liver triglyceride content of HSLAKO mice compared with control mice;and body weight of 8-month-old HSLAKO mice was significantly lower than that of the control mice,while liver weight and triglyceride fat content were significantly higher than those of the control mice.H & E liver histological staining confirmed that liver steatosis happened in 8-month-old HSLAKO mice.This showed that only the deficiency of HSL in adipose tissue can cause age-dependent steatosis of liver tissue in systemic deficiency of HSL.(4)HSLAKO mice developed age-dependent lipoatrophy and inflammation of adipose tissue in white adipose tissue.Study of the adipose tissue of HSLAKO and control mice found that there was no difference in the weight of adipose tissue(gonads,perirenal,mesentery,and subcutaneous)between 3-month-old HSLAKO and control mice,but 8-month-old HSLAKO mice was significantly lower than those in the control mice.Morphological studies found that HSL deficiency leads to adipocyte heterogeneity,that is,cell diameters in HSL-deficient adipose tissues differ significantly.In addition,the absence of HSL caused a large number of macrophages to invade the adipose tissue,which manifested as a severe adipose tissue inflammatory response.(5)HSLAKO mice experienced systemic steady-state changes of energy.The insulin sensitivity test results showed that compared with the control group,the 3-month-old HSLAKO mice had increased insulin sensitivity,but at 8 months of age showed more severe insulin resistance symptoms than the control group;but both There was no significant difference in glucose tolerance.Intramuscular triglyceride content test results showed that the triglyceride content in skeletal muscle of HSLSKO and HSLAKO mice was significantly higher than that in the control group.The above results indicate that HSLAKO mice undergo steady-state changes in systemic energy.(6)HSLAKO mice have low ability of fatty acid oxidation and low-density lipoprotein secretion.Blood 3-hydroxybutyrate(3-HB)levels,Rt-PCR results of fatty acid oxidation-related genes in liver tissue,and fatty acid oxidation results of liver sections showed that liver fatty acid oxidation levels of HSLAKO mice were lower than those of the control group.This probably one of the causes of liver steatosis.The results of very low-density lipoprotein(VLDL)in liver secretion showed that the amount of VLDL produced in HSLAKO mice was significantly lower than that in the control group.This may be another cause of liver steatosis in HSLAKO mice.(7)Hepatic steatosis in HSLAKO mice has no correlation with hepatocyte damage,hepatitis and liver fibrosis.Although HSLAKO mice develop age-dependent fatty liver,their blood ALT levels,the m RNA expression levels of pro-inflammatory cytokines(TNF?,IL-6),M1-type macrophage markers(iNOS,Cxcl9 and Cxcl10)and fibers fibrosis marker factors(MMP9,TGF?1 and ?-SMA)showed no significant differences.This indicates that HSLAKO mice have only simple fatty lesions.The results of the above studies indicate that age-dependent liver steatosis and insulin resistance in HSL-deficient mice are caused by the loss of HSL leading to age-dependent lipoatrophy of the adipose tissue and inflammation of the adipose tissue,which in turn leads to systemic diseases including hepatic steatosis.The occurrence of metabolic syndrome has nothing to do with the loss of HSL in liver tissue.