TFEB and proteostasis deficiencies: However, additional stresses such as smoking and possibly genetic mutations in digestive enzymes can incapacitate or overwhelm the adaptive and protective UPR resulting in a pathologic UPR and pancreatitis, reaffirming that lifestyle factors can cause ER protein folding disorders; (iii) impaired TFEB-mediated lysosomal biogenesis and autophagy play critical roles in promoting the pathogenesis of pancreatitis; and (iv) chronic alcohol consumption alters pancreatic endocrine function contributing to increasing metabolic comorbidities among people living with HIV.