Altered Mitochondrial Quality Control in Rats with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) Induced by High-Fat Feeding

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) is defined as the presence of hepatic steatosis in addition to one of three metabolic conditions: overweight/obesity, type 2 diabetes mellitus, or metabolic dysregulation. Chronic exposure to excess dietary fatty acids may cause hepatic steatosis and metabolic disturbances. The alteration of the quality of mitochondria is one of the factors that could contribute to the metabolic dysregulation of MAFDL. This study was designed to determine, in a rodent model of MAFLD, the effects of a long-term high-fat diet (HFD) on some hepatic processes that characterize mitochondrial quality control, such as biogenesis, dynamics, and mitophagy. To mimic the human manifestation of MAFLD, the rats were exposed to both an HFD and a housing temperature within the rat thermoneutral zone (28–30 °C). After 14 weeks of the HFD, the rats showed significant fat deposition and liver steatosis. Concomitantly, some important factors related to the hepatic mitochondrial quality were markedly affected, such as increased mitochondrial reactive oxygen species (ROS) production and mitochondrial DNA (mtDNA) damage; reduced mitochondrial biogenesis, mtDNA copy numbers, mtDNA repair, and mitochondrial fusion. HFD-fed rats also showed an impaired mitophagy. Overall, the obtained data shed new light on the network of different processes contributing to the failure of mitochondrial quality control as a central event for mitochondrial dysregulation in MAFLD.

High‐fat diet affects autophagy and mitochondrial compartment in rat Harderian gland

“…In the present study we have investigated for the first time the cellular response induced by intake of HFD in rat HG, focusing on the mitochondrial compartment. The use of thermoneutral housing (28−30°C) in association with HFD exacerbates lipid accumulation in topic and ectopic tissues, when compared to standard housing temperature (22−24°C) (Cioffi et al, 2022). Thus, the rats fed with HFD showed greater body weight and adiposity gains than the control animals, since they accumulate much more fat in adipose tissue, and a reduced Respiratory Quotient indicating a shift in metabolism toward utilization of lipids.…”

“…To study the response elicited by the lipid overload in rat HG, we have housed the animals in thermoneutral conditions (28−30°C) in association with a high fat diet (HFD). The thermoneutrality exacerbates lipid accumulation in topic and ectopic tissues when compared to standard housing temperature (22−24°C) (Cioffi et al, 2022). At the end of the treatment, an ultrastructural and biochemical analyses on rat HG were carried out.…”

“…,b), OPA1 (Figure 7a,c), and Drp1 (Figure 7a,d), protein levels in HFD rat HG were significantly increased as compared to controls.4 | DISCUSSIONIn the present study we have investigated for the first time the cellular response induced by intake of HFD in rat HG, focusing on the mitochondrial compartment. The use of thermoneutral housing (28−30°C) in association with HFD exacerbates lipid accumulation in topic and ectopic tissues, when compared to standard housing temperature (22−24°C)(Cioffi et al, 2022). Thus, the rats fed with HFD showed greater body weight and adiposity gains than theF I G U R E 2Beclin 1 (a, b), ATG5 (a, c), ATG16 L1 (a, d), and p62 (a, f) Western blot detection in HG from control and HFD rats.…”

NAFLD: Mechanisms, Treatments, and Biomarkers

“…In a vicious cycle, damaged mitochondria become dysfunctional, causing impaired oxidative phosphorylation, and increased production of ROS. Excessive and uncontrolled production of ROS in the mitochondria damages mitochondrial components, including membranes, proteins, and mDNA, and triggers the mitochondrial quality control (MQC) [ 129 , 130 , 131 ]. MQC includes biogenesis, fission, fusion, and mitophagy.…”

Low abundance of mitophagy markers is associated with reactive oxygen species overproduction in cows with fatty liver and causes reactive oxygen species overproduction and lipid accumulation in calf hepatocytes

“…High levels of FFA in cells render the mitochondria prone to overproduction of reactive oxygen species (ROS; Zorov et al, 2014), which can lead to mitochondrial damage (Sanz et al, 2006) and aggravate hepatic lipidosis (Rector et al, 2010). Thus, timely elimination of damaged mitochondria contributes to reduction in ROS production and helps maintain lipid metabolism homeostasis (Rector et al, 2010;Zhao et al, 2021;Cioffi et al, 2022).…”