Endonuclease G restores lipid homeostasis in spontaneously hypertensive rats: implications for mitochondrial function

The mitochondrial endonuclease G (Endog) is best known for its roles in apoptosis and mitochondrial DNA maintenance, but accumulating evidence suggests broader metabolic functions. The spontaneously hypertensive rat (SHR) carries a natural loss-of-function mutation in Endog associated with mitochondrial dysfunction and left ventricular hypertrophy. We hypothesized that impaired mitochondrial oxidative metabolism, causing lipid dysregulation will be reversed by Endog restoration in the SHR.

To determine the metabolic consequences of Endog restoration, we used two complementary rat models: (1) male SHR-Endog transgenic rats and (2) male SHR.BN-Endog congenic rats expressing wild-type Endog, each compared with their respective controls. We quantified adiposity, lipid and glucose homeostasis, liver and cardiac lipid accumulation, and white (WAT) and brown adipose tissue (BAT) metabolism.

Endog restoration in both transgenic and congenic rats led to reduced adiposity, lower serum triglycerides and non-esterified fatty acids (NEFA), and decreased ectopic lipid deposition in liver and heart. These improvements were accompanied by enhanced NEFA re-esterification in WAT, increased insulin-stimulated lipogenesis, and augmented palmitate oxidation in BAT. Systemic glucose and insulin levels were not significantly affected.

Restoration of Endog expression improves lipid homeostasis and adipose tissue metabolic function in SHR. These findings suggest a role for Endog in the regulation of systemic lipid metabolism, with potential implications for mitochondrial-related metabolic processes.