Hepatic VLDL assembly is disturbed in a rat model of nonalcoholic fatty liver disease: is there a role for dietary coenzyme Q?

Abstract

The overproduction of very-low-density lipoprotein (VLDL) is a characteristic feature of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to use a high-fat diet-induced model of NAFLD in rats to investigate 1) the influence of the disease on hepatic VLDL processing in the endoplasmic reticulum and 2) the potential modulatory effects of dietary coenzyme Q (CoQ). Rats were fed a standard low-fat diet (control) or a diet containing 35% fat (57% metabolizable energy). After 10 wk, high-fat diet-fed animals were divided into three groups: the first group was given CoQ9 (30 mg*kg body wt(-1)*day(-1) in 0.3 ml olive oil), the second group was given olive oil (0.3 ml/day) only, and the third group received no supplements. Feeding (3 high-fat diets and the control diet) was then continued for 8 wk. In all high-fat diet-fed groups, the content of triacylglycerol (TG) and cholesterol in plasma VLDL, the liver, and liver microsomes was increased, hepatic levels of apolipoprotein B48 were raised, and the activities of microsomal TG transfer protein and acyl CoA:cholesterol acyltransferase were reduced. These findings provide new evidence indicating that VLDL assembly and the inherent TG transfer to the endoplasmic reticulum are altered in NAFLD and suggest a possible explanation for both the overproduction of VLDL associated with the condition and the disease etiology itself. Dietary CoQ caused significant increases in apolipoprotein B mRNA and microsomal TG levels and altered the phospholipid content of microsomal membranes. These changes, however, may not be beneficial as they may lead to the secretion of larger, more atherogenic VLDL.

PGC-1α overexpression results in increased hepatic fatty acid oxidation with reduced triacylglycerol accumulation and secretion

“…However, the reduction in apoB-48 protein could be sufficient to explain the decreases in plasma TAG. ApoB-48 represents the dominant apoB protein variant in rat liver, is less susceptible to intracellular degradation than apoB-100 (35), and has been observed to be preferentially increased over apoB-100 in animals with increased VLDL-TAG due to a chronic high-fat diet (5). However, no decrease in either apoB protein is required for reduced TAG secretion, as observed by decreased media TAG with no reduction in apoB-48 or apoB-100 protein expression in rat hepatocytes overexpressing CPT-1a (38).…”

LXR agonist increases apoE secretion from HepG2 spheroid, together with an increased production of VLDL and apoE-rich large HDL

“…One of the aspects of this alteration is the increased production of VLDL particles. In the state of hepatic steatosis, not only triglycerides but also cholesterol accumulate in hepatocytes [15], and the oxidative stress which increases in hepatic steatosis [16] transforms the cholesterol to oxysterol, which is a natural ligand for LXR. Because the production of apoE is one of the important determinants for the secretion of VLDL or VLDL-TG from the liver [3], the upregulation of apoE gene together with the increased production of triglycerides [17,18] by LXR activation facilitates the production of VLDL particles, resulting in the atherogenic lipid profile of the metabolic syndrome.…”

Mitochondria and Redox Signaling in Steatohepatitis

“…Additionally, the observation of reduced systemic coenzyme Q10 levels in patients with NAFLD (223) has lead to limited investigation of the effects of dietary supplementation of coenzyme Q. Coenzyme Q10 supplementation has been observed to lower oxidative stress and markers of inflammation in a mouse, without modulating lipid peroxidation or improving systemic insulin resistance (195). Additionally, coenzyme Q9 monomethyl ether administration increased VLDL assembly in rats with high-fat-diet-induced steatosis (22,182), with no observed improvement in NAFLD or systemic insulin resistance (182).…”