Impacts of non- and whole-fat milk supplementation on metabolic dysfunction-associated steatotic liver disease (MASLD) in C57BL/6 mice
Creators: Berg, Emily
Publisher: name: University of Alberta Library
Year: 2024

<p>The pathophysiology behind metabolic dysfunction-associated steatotic liver disease (MASLD) and mechanisms underlying the progression of the disease are highly complex, complicating treatment options, leaving diet and weight loss as the standard of care. Functional foods can mitigate MASLD progression by improving glucose and lipid homeostasis with many studies focusing on the role of dairy products; however, the mechanism of action has not been elucidated. </p>

<p>This study aims to compare MASLD-related outcomes after feeding non- (NFM) versus whole-fat milk (WFM) in a high-fat diet (HFD)-induced obese mouse model. I hypothesize that (1) both WFM and NFM will significantly reduce diet-induced hepatic lipid accumulation and prevent the progression of early-stage MASLD in obese, male C57BL/6 mice but via different mechanisms and that (2) increased capacity for substrate uptake and metabolism in skeletal muscle may act as a mediator of reduced hepatic steatosis. </p>

<p>After 8 weeks of providing 0.425 mL for 5 days per week of either NFM or WFM milk to mice, mice were euthanized, and tissues collected in a fasted state. NFM significantly reduced body weight (BW) gain and fat mass, hepatic triglyceride (TG), lipid droplet (LD) number, and total area covered by LD compared to HFD (p &lt; 0.05). This was accompanied by an increase in hepatic mitochondrial complex abundance (p &lt; 0.05) and a trend towards enhanced microsomal triglyceride transfer protein (MTP) abundance (p = 0.076). WFM trended towards a reduction in total area covered by LD (p = 0.051) compared to HFD but had significantly higher TG compared to NFM (p &lt; 0.05). Enzymes involved in de novo lipogenesis were increased in WFM, including fatty acid binding protein 4 (FABP4) (p = 0.059), fatty acid synthase (FAS) (p &lt; 0.05), and the proportion of phosphorylated acetyl-CoA carboxylase (p-ACC / ACC) (p &lt; 0.05) compared to NFM. There was also an increase in carnitine palmitoyl transferase 1a(CPT1a) protein abundance (p &lt; 0.05) in WFM compared to HFD and Opa1 expression (p &lt; 0.05) in WFM compared to NFM. </p>

<p>In skeletal muscle, no significant differences were seen in protein kinase B (Akt), or adenosine-monophosphate (AMP) activated kinase (AMPK), which are enzymes involved in glucose metabolism. Within lipid metabolism pathways, CD36 abundance was down regulated in both WFM and NFM compared to HFD (p &lt; 0.05), and Sirtuin-1 (SIRT1) abundance was enhanced in WFM compared to NFM (p &lt; 0.05). No differences were seen in CPT1a and peroxisome proliferator-activated receptor-gamma coactivator 1a (PGC1a). </p>

<p>Overall, NFM displayed greater beneficial effects than WFM in mitigating MASLD progression by increasing the capacity for hepatic oxidative phosphorylation and fatty acid (FA) export, which were associated with reduced hepatic fat accumulation. Skeletal muscle metabolism did not display an enhanced capacity for substrate uptake, and only WFM demonstrated an enhanced abundance of SIRT1 with no further alterations downstream. <br>
In conclusion, this thesis provides evidence that NFM is may be superior to WFM in promoting beneficial effects in an HFD-induced obese mouse model through reduced hepatic lipid accumulation and improved utilization of FA. These results may outline a potential tool for early intervention to prevent and attenuate the progression of MASLD. </p>