Lowering apolipoprotein CIII protects against high-fat diet–induced metabolic derangements

Abstract

Increased levels of apolipoprotein CIII (apoCIII), a key regulator of lipid metabolism, result in obesity-related metabolic derangements. We investigated mechanistically whether lowering or preventing high-fat diet (HFD)–induced increase in apoCIII protects against the detrimental metabolic consequences. Mice, first fed HFD for 10 weeks and thereafter also given an antisense (ASO) to lower apoCIII, already showed reduced levels of apoCIII and metabolic improvements after 4 weeks, despite maintained obesity. Prolonged ASO treatment reversed the metabolic phenotype due to increased lipase activity and receptor-mediated hepatic uptake of lipids. Fatty acids were transferred to the ketogenic pathway, and ketones were used in brown adipose tissue (BAT). This resulted in no fat accumulation and preserved morphology and function of liver and BAT. If ASO treatment started simultaneously with the HFD, mice remained lean and metabolically healthy. Thus, lowering apoCIII protects against and reverses the HFD-induced metabolic phenotype by promoting physiological insulin sensitivity.

Apolipoprotein CIII Reduction Protects White Adipose Tissues against Obesity-Induced Inflammation and Insulin Resistance in Mice

“…Lipolysis is inhibited by insulin and stimulated by catecholamines, and functional studies in isolated adipocytes from SAT and VAT, from all experimental groups, revealed that lowering apoCIII normalizes these responses. This clearly shows that there is a restored insulin sensitivity in WAT, as previously shown in liver and BAT, which is a key factor for an efficient glucose and lipid metabolism [9].…”

“…Hypertriglyceridemia often occurs in obesity and there is a positive correlation between apolipoprotein CIII (apoCIII) and triglycerides [ 4 , 5 , 6 ]. In recent years apoCIII has become interesting as a co-actor in the development of overweight and insulin resistance [ 7 , 8 , 9 ]. During conditions of insulin resistance, there is a parallel increase in intra-islet apoCIII associated with local islet inflammation and β-cell dysfunction/apoptosis [ 10 ].…”

“…It has been shown that both transgenic mice, overexpressing apoCIII, and mice with a complete deficiency of the apolipoprotein have a more pronounced diet-induced obesity (DIO) [ 5 , 6 , 11 ]. However, decreasing apoCIII has beneficial metabolic effects [ 9 , 10 , 12 ]. The degree of apoCIII suppression required to induce protective effects against metabolic derangements ranges from 40 to 98%, depending on species, strains, diets and genetic factors [ 9 , 10 , 12 , 13 , 14 ].…”

“…However, decreasing apoCIII has beneficial metabolic effects [ 9 , 10 , 12 ]. The degree of apoCIII suppression required to induce protective effects against metabolic derangements ranges from 40 to 98%, depending on species, strains, diets and genetic factors [ 9 , 10 , 12 , 13 , 14 ]. When C57BL6/j mice on high-fat diet (HFD) were treated with antisense oligonucleotides (ASOs) against apoCIII, either directly from start or after 10 weeks on the diet, the harmful effects of the HFD were eliminated in both groups [ 9 ].…”

“…The underlying mechanisms behind these positive results of lower apoCIII levels are complex and involve increased lipase activity and receptor-mediated hepatic uptake of lipids, normalization of insulin sensitivity, increase in hepatic fatty acid oxidation and ketogenesis, while de novo lipogenesis and gluconeogenesis are inhibited [ 9 ]. In addition, there are several pieces of evidence for a metabolically more active brown adipose tissue with an increase in expression levels of β3-adrenergic receptor, body temperature, lipoprotein lipase activity and upregulation of thermogenic genes [ 9 ].…”