APOC3 Protein Is Not a Predisposing Factor for Fat-induced Nonalcoholic Fatty Liver Disease in Mice

Abstract

Edited by Jeffrey E. PessinNonalcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in liver, is prevalent in obesity. Genetic factors that link obesity to NAFLD remain obscure. Apolipoprotein C3 (APOC3) is a lipid-binding protein with a pivotal role in triglyceride metabolism. Humans with APOC3 gain-of-function mutations and mice with APOC3 overproduction are associated with hypertriglyceridemia. Nonetheless, it remains controversial whether APOC3 is culpable for diet-induced NAFLD. To address this fundamental issue, we fed APOC3-transgenic and wild-type littermates a high fructose diet or high fat diet, followed by determination of the effect of APOC3 on hepatic lipid metabolism and inflammation and the progression of NAFLD. To gain mechanistic insight into NAFLD, we determined the impact of APOC3 on hepatic triglyceride synthesis and secretion versus fatty acid oxidation. APOC3-transgenic mice were hypertriglyceridemic, culminating in marked elevation of triglycerides, cholesterols, and nonesterified fatty acids in plasma. Despite the prevailing hypertriglyceridemia, APOC3-transgenic mice, relative to wild-type littermates, had similar weight gain and hepatic lipid content without alterations in hepatic expression of key genes involved in triglyceride synthesis and secretion and fatty acid oxidation. APOC3-transgenic and wild-type mice had similar Kupffer cell content without alterations in hepatic expression of pro-and anti-inflammatory cytokines. APOC3 neither exacerbated dietinduced adiposity nor aggravated the degree of steatosis in high fructose or high fat-fed APOC3-transgenic mice. These effects ensued independently of weight gain even after 10-month high fat feeding. We concluded that APOC3, whose dysregulation is liable for hypertriglyceridemia, is not a predisposing factor for linking overnutrition to NAFLD in obesity. Nonalcoholic fatty liver disease (NAFLD)4 is characterized by excessive lipid deposition in the liver of subjects with little alcohol consumption. Patients with NAFLD are at heightened risk of developing steatohepatitis with potential complications of fibrosis and cirrhosis (1-4). Currently, NAFLD affects about 30% of the general population, and its prevalence is increasing along with the rising epidemic of obesity in both adults and children (1, 5-10). Although it is known that NAFLD results from increased lipogenesis and decreased fatty acid oxidation in the liver, accompanied often by hepatic overproduction of TG-rich very low density lipoprotein (VLDL-TG), genetic factors that tip the balance of these three intertwining pathways in hepatic lipid metabolism at the expense of NAFLD are incompletely characterized.Apolipoprotein C3 (APOC3) (79 amino acids in length) is one of the most abundant apolipoproteins in the blood, where it is present as an exchangeable moiety between high density lipoproteins (HDLs) and triglyceride (TG)-rich particles, such as VLDL and chylomicrons (11). Secreted mainly from the liver and to a lesser extent from the intestine, AP...

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“…However, conflicting evidence about the causal link between ApoCIII expression and hepatic steatosis do exist. In particular, the degree of liver steatosis and inflammation of ApoCIII transgenic mice after high fat diet for up to 10 months was similar to the wild‐type littermates . Moreover, data from clinical observations showed no association between the two ApoCIII promoter region polymorphisms, C‐482 T and T‐455C, and the development of NAFLD …”

“…In particular, the degree of liver steatosis and inflammation of ApoCIII transgenic mice after high fat diet for up to 10 months was similar to the wild-type littermates. 68 Moreover, data from clinical observations showed no association between the two ApoCIII promoter region polymorphisms, C-482 T and T-455C, and the development of NAFLD. [69][70][71][72][73] 5.3 | ApoCIII, dysfunctional HDL particles, and attenuated antiglycemic effect HDL particles have multiple beneficial actions including the promotion of cholesterol transport from peripheral tissues to the liver, antioxidant, antithrombotic, and antifibrotic properties, and the modulation of inflammation.…”

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

“…ApoC3 variants clearly impact plasma TG levels but they do not seem to have a consistent effect on hepatic steatosis [ [83] , [84] , [85] , [86] , [87] ]. In line, overexpression of ApoC3 in HFD-fed mice did not change steatosis despite markedly elevating plasma triglycerides due to impaired TG clearance [ 88 ]. Thus, ApoC3 more likely plays a role in NAFLD-associated dyslipidemia.…”

Pathogenesis of non-alcoholic fatty liver disease in children and adolescence: From “two hit theory” to “multiple hit model”

“…The consequence of the reduced TG clearance is an increase in residual particles of chylomicrons, that will lead to higher levels of circulating chylomicron remnants, which are especially cleared by the liver through a receptor-mediated process[ 77 , 78 ]. However, a recent study of APOC3 transgenic mice suggested that APOC3 dysregulation is not a predisposing factor for linking over-nutrition to NAFLD in obesity[ 79 ].…”