Impaired VLDL assembly: a novel mechanism contributing to hepatic lipid accumulation following ovariectomy and high-fat/high-cholesterol diets?

The aim of the present study was to identify molecular mechanisms involved in liver fat and cholesterol accumulation in ovariectomised (Ovx) rats fed with high-cholesterol diets. VLDL assembly and bile acid metabolism were specifically targeted. After being either Ovx or sham-operated, the rats were fed a standard diet or a high-fat diet containing 0, 0·25 or 0·5 % cholesterol for 6 weeks. Although Ovx rats exposed to dietary cholesterol intake accumulated the greatest amount of hepatic fat and cholesterol, plasma cholesterol levels were lower (P< 0·05) in these animals than in the corresponding control rats. Accompanying this observation, ovariectomy and dietary cholesterol intake resulted in a down-regulation (P< 0·05) of the expression of genes associated with VLDL assembly, including microsomal TAG transfer protein, diacylglycerol acyltransferase 2, acyl-CoA:cholesterol acyltransferase 2 and apoB-100 as well as genes associated with bile acid metabolism including farnesoid X receptor and bile salt export pump (P< 0·01). These results indicate that high-fat/high-cholesterol diets and ovariectomy concomitantly disrupt hepatic lipid output through defects in VLDL assembly and, most probably, secretion. The results also point to a defect in hepatic bile acid secretion. The present study offers novel insights into intrahepatic lipid metabolism, which may be relevant to metabolic complications found in postmenopausal women.

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Role of Nrf2 in the alteration of cholesterol and bile acid metabolism-related gene expression by dietary cholesterol in high fat-fed mice

Journal of Clinical Biochemistry and Nutrition ◽

10.3164/jcbn.13-92 ◽

2014 ◽

Vol 54 (2) ◽

pp. 90-94 ◽

Cited By ~ 18

Author(s):

Toshinori Kamisako ◽

Yuji Tanaka ◽

Yoshizumi Kishino ◽

Takanori Ikeda ◽

Kazuo Yamamoto ◽

...

Keyword(s):

Gene Expression ◽

Bile Acid ◽

Acid Metabolism ◽

Dietary Cholesterol ◽

Bile Acid Metabolism ◽

Related Gene ◽

High Fat

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Estradiol treatment or modest exercise improves hepatic health and mitochondrial outcomes in female mice following ovariectomy

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00013.2021 ◽

2021 ◽

Author(s):

Kelly N. Z. Fuller ◽

Colin S. McCoin ◽

Alex T. Von Schulze ◽

Claire J. Houchen ◽

Michael A. Choi ◽

...

Keyword(s):

Bile Acid ◽

Mitochondrial Function ◽

High Fat Diet ◽

Acid Metabolism ◽

Bile Acid Metabolism ◽

High Fat ◽

Estradiol Treatment ◽

Respiratory Capacity ◽

Female Mice ◽

Mitochondrial Respiratory

We recently reported that compared to males, female mice have increased hepatic mitochondrial respiratory capacity and are protected against high-fat diet-induced steatosis. Here we sought to determine the role of estrogen in hepatic mitochondrial function, steatosis, and bile acid metabolism in female mice, as well as investigate potential benefits of exercise in the absence or presence of estrogen via ovariectomy (OVX). Female C57BL mice (n=6 per group) were randomly assigned to sham surgery (Sham), ovariectomy (OVX), or OVX plus estradiol replacement therapy (OVX+Est). Half of the mice in each treatment group were sedentary (SED) or had access to voluntary wheel running (VWR). All mice were fed a high-fat diet (HFD) and were housed at thermoneutral temperatures. We assessed isolated hepatic mitochondrial respiratory capacity using the Oroboros O2k with both pyruvate and palmitoylcarnitine as substrates. As expected, OVX mice presented with greater hepatic steatosis, weight gain, and fat mass gain compared to Sham and OVX+Est animals. Hepatic mitochondrial coupling (Basal/State 3 respiration) with pyruvate was impaired following OVX, but both VWR and estradiol treatment rescued coupling to levels greater than or equal to Sham animals. Estradiol and exercise also had different effects on liver electron transport chain protein expression depending on OVX status. Markers of bile acid metabolism and excretion were also impaired by ovariectomy but rescued with estradiol add-back. Together our data suggest that estrogen depletion impairs hepatic mitochondrial function and liver health, and that estradiol replacement and modest exercise can aid in rescuing this phenotype.

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