Title of project

Targeting hepatic lipid accumulation by dietary interventions – the metabolic impact of intermittent carbohydrate restriction and short- and medium-chain fatty acids

Abstract

Non-alcoholic fatty liver disease is defined by fat accumulation in the liver (steatosis) exceeding 5.5% with an estimated prevalence of 25% in the adult population. Excess accumulation of fat in the liver is associated with dysregulated glucose metabolism and dyslipidemia. Reducing excess liver fat content is thus an appealing therapeutic goal in the prevention and treatment of metabolic diseases.

Our own preliminary findings and recent dietary studies have shown that high-fat, lowcarbohydrate intake is associated with reduced liver fat accumulation and improved regulation of whole-body lipid and glucose metabolism in patients with type 2 diabetes and healthy individuals with obesity. This is presumably, in part, due to increased intrahepatic and wholebody fatty acid (FA) utilization caused by reduced dietary carbohydrate availability and increased fat availability. However, a challenge of reduced compliance to prolonged high-fat, low-carbohydrate intake was recently evidenced, emphasizing the need for alternative dietary strategies. Since eucaloric carbohydrate restriction for only one day reduces hepatic glycogen and fat content, intermittent carbohydrate restriction might provide a dietary strategy to lower glucose storage and increase intrahepatic and whole-body FA utilization, which may have beneficial effects on liver fat accumulation and glycemic regulation the following days. Another way to stimulate hepatic FA oxidation and thereby reduce hepatic fat content may be dietary supplementation with short- (SCFA) and medium-chain FA (MCFA) due to their different pattern of absorption and oxidation compared with long-chain FA.

Thus, the aim of this PhD study is to evaluate the metabolic effects of specific dietary interventions designed to target liver fat metabolism and, thereby, whole-body lipid and glucose metabolism. Two shorter-term human intervention studies will be performed to evaluate the effects of 1) intermittent carbohydrate restriction and 2) supplementation with SCFA and MCFA. The hypothesis is that increasing hepatic FA utilization, by depriving dietary carbohydrates or providing SCFA and MCFA, will lower hepatic lipid accumulation and improve glycemic control. The proposed studies are directly implementable in a free-living setting, and their completion will increase the knowledge of regulatory mechanisms within the liver and the role of hepatic metabolism in whole-body lipid and glucose metabolism, relevant for individuals with metabolic syndrome and diabetes, and the clinicians involved in their treatment. Furthermore, knowledge gained through these studies will be relevant to the life science industry such as Arla Foods amba by identifying potential health benefits of high-fat, low-carbohydrate dairy products and SCFA and MCFA substantially abundant in milk fat.