UC Merced

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than 30% of the global population and primarily afflicts individuals with metabolic syndrome (MetS) due to their overlapping risk factors. MetS is defined as the presence of three or more of the following risk factors: (1) abdominal obesity, (2) atherogenic dyslipidemia, (3) hyperglycemia with or without insulin resistance, (4) hypertension, (5) proinflammatory state, and (6) prothrombotic state. Currently, there is no FDA-approved treatment for MASLD; therefore, the first line of non-pharmaceutical defense is caloric restriction (CR). However, failure to maintain a caloric restriction diet among obese individuals is extremely high, resulting in body mass regain (BMr). BMr following CR has been shown to exacerbate impaired lipid metabolism by inducing excess hepatic fat accumulation and causing an imbalance between lipid availability and its utilization. This impairment in hepatic lipid metabolism may induce MASLD. Subsequently, the accumulation of excess lipids in the liver promotes the production of reactive oxygen species (ROS) through a disequilibrium in redox signaling. This shift catalyzes the transition between MASLD to a progressive onset of metabolic dysfunction-associated steatohepatitis (MASH). The benefits of CR on MetS and MASLD are well established; however, the literature lacks focused studies on the pathways associated with lipid metabolism and redox signaling after BMr. In this dissertation, the Otsuka Long Evans Tokushima Fatty (OLETF) rat was used as a model of MetS due to its similarities to the human conditions. This model was used to investigate the effects of partial and complete BM regain following caloric restriction on hepatic lipid metabolism, redox balance, and thyroid hormone signaling during MetS. We demonstrated that: (1) partial BMr induced hepatic fat accumulation via elevated triglycerides with saturated fatty acids, downregulated fatty acid oxidation proteins, and reversed the benefits induced by CR suggesting that even partial regain of BM (PR) can promote MASLD, (2) PR impairs TH signaling, uncoupling TH signaling and its regulation of hepatic lipid metabolism via a reduction in TH receptor beta (THRβ), associated with changes in the hepatic lipidome (ACars, CLs, LPCs, PCs, and PIs), all of which induce the progression of MASLD to MASH by increasing hepatic injury, and (3) complete BM regain during early Mets increased 4-hydroxenenol (4HNE) despite elevated catalase (CAT) activity demonstrating that complete regain induced oxidative injury associated with impaired hepatic lipid metabolism. Collectively, this dissertation provides insight into the detriments of BMr (complete or partial) following CR on hepatic lipid metabolism, oxidative injury, and TH signaling during MetS.