Amino acid residues L261, W264, F265, L268, and V269 of apolipoprotein E4 critically regulate adipose tissue metabolism

TL;DR

A specific region of the APOE4 protein affects fat tissue metabolism, offering a new approach to treat obesity and related conditions.

Contribution

The study identifies specific amino acid residues in APOE4 that regulate adipose tissue metabolism and hypertriglyceridemia.

Findings

APOE4mut1 stimulates brown adipose tissue metabolism through non-shivering thermogenesis and oxidative phosphorylation.

APOE4mut1 enhances mitochondrial activity in white adipose tissue, overriding the effects of wild-type APOE4.

Targeted mutagenesis of APOE4 residues 260–270 may offer therapeutic benefits for metabolic syndrome.

Abstract

Apolipoprotein E (APOE) plays a tissue-specific role in diet-induced obesity: brain-expressed APOE promotes obesity, while hepatic APOE appears protective. Physiological plasma APOE levels facilitate clearance of atherogenic lipoproteins; however, supraphysiological levels induce hypertriglyceridemia and impair cholesterol clearance. APOE-induced hypertriglyceridemia has been linked to its carboxyl-terminal region (amino acids 260–270), particularly residues L261, W264, F265, L268, and V269. A bioengineered APOE4 variant, APOE4mut1, where these residues are substituted with alanine, promotes cholesterol clearance without inducing hypertriglyceridemia at any level of expression. This study examined APOE4mut1 effects on adipose tissue metabolism in vivo. Wild-type (C57BL/6) and APOE4knock-in mice were fed a Western-type diet for varying periods and infected with adenoviruses expressing APOE4 (AdAPOE4), APOE4mut1 (AdAPOE4mut1), or only the green fluorescent protein (GFP) (AdGFP). AdAPOE4mut1 infection of C57BL/6 mice fed a Western-type diet for 8 or 24 weeks stimulated brown adipose tissue (BAT) metabolism by inducing non-shivering thermogenesis and oxidative phosphorylation. In contrast, AdAPOE4 suppressed thermogenesis in this tissue. In white adipose tissue (WAT), AdAPOE4mut1 was able to stimulate thermogenesis after 24 weeks of feeding. This stimulatory effect in WAT was dominant over wild-type APOE4, since APOE4mut1 similarly enhanced mitochondrial activity in WAT of APOE4knock-in mice. These findings suggest that amino acid residues 260–270 of APOE4 critically regulate adipose tissue metabolism, in addition to their previously reported role in APOE-induced hypertriglyceridemia. Targeted mutagenesis within this region offers a potential therapeutic strategy for addressing hypertriglyceridemia and obesity in metabolic syndrome.

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